Research ArticleGeneticsInfectious disease
Open Access | 
10.1172/jci.insight.159491
Immunogenetics associated with severe coccidioidomycosis
Amy P. Hsu,1,2 Agnieszka Korzeniowska,1 Cynthia C. Aguilar,1 Jingwen Gu,3 Eric Karlins,3 Andrew J. Oler,3 Gang Chen,4 Glennys V. Reynoso,1 Joie Davis,1 Alexandria Chaput,5 Tao Peng,5 Ling Sun,4,6 Justin B. Lack,7,8 Derek J. Bays,9 Ethan R. Stewart,9 Sarah E. Waldman,9 Daniel A. Powell,5,10 Fariba M. Donovan,5,11 Jigar V. Desai,1 Nima Pouladi,12,13 Debra A. Long Priel,14 Daisuke Yamanaka,1,15 Sergio D. Rosenzweig,16 Julie E. Niemela,16 Jennifer Stoddard,16 Alexandra F. Freeman,1 Christa S. Zerbe,1 Douglas B. Kuhns,14 Yves A. Lussier,12,13 Kenneth N. Olivier,17 Richard C. Boucher,4 Heather D. Hickman,1 Jeffrey Frelinger,5,18 Joshua Fierer,19,20 Lisa F. Shubitz,5 Thomas L. Leto,1 George R. Thompson III,9,21 John N. Galgiani,5,11 Michail S. Lionakis,1 and Steven M. Holland1
1Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases (NIAID), NIH, Bethesda, Maryland, USA.
2Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, Maryland, USA.
3Bioinformatics and Computational Biosciences Branch, Office of Cyber Infrastructure and Computational Biology, NIAID, NIH, Bethesda, Maryland, USA.
4Marsico Lung Institute and Cystic Fibrosis Research Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
5Valley Fever Center for Excellence, University of Arizona College of Medicine–Tucson, Tucson, Arizona, USA.
6Department of Respiratory and Critical Care Medicine, Laboratory of Pulmonary Immunology and Inflammation, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China.
7NIAID Collaborative Bioinformatics Resource, NIAID, NIH, Bethesda, Maryland, USA.
8Advanced Biomedical Computational Science, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Frederick, Maryland, USA.
9Department of Internal Medicine, Division of Infectious Diseases, UC Davis Health, Sacramento, California, USA.
10Department of Immunobiology, University of Arizona, Tucson, Arizona, USA.
11Department of Medicine, University of Arizona College of Medicine–Tucson, Tucson, Arizona, USA.
12Center for Biomedical Informatics and Biostatistics and
13The Center for Applied Genetics and Genomic Medicine, Department of Medicine, University of Arizona, Tucson, Arizona, USA.
14Neutrophil Monitoring Laboratory, Applied/Developmental Research Directorate, Leidos Biomedical Research, Inc, Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA.
15Laboratory for Immunopharmacology of Microbial Products, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo, Japan.
16Immunology Service, Department of Laboratory Medicine, Clinical Center and
17Laboratory of Chronic Airway Infection, Pulmonary Branch, National Heart, Lung, and Blood Institute, NIH, Bethesda, Maryland, USA.
18Department of Immunobiology, University of Arizona, Tucson, Arizona, USA.
19VA HealthCare San Diego, San Diego, California, USA.
20Division of Infectious Diseases, Departments of Pathology and Medicine, School of Medicine, University of California San Diego, La Jolla, California, USA.
21Department of Medical Microbiology and Immunology, University of California Davis, Davis, California, USA.
Address correspondence to: Steven M. Holland, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Disease, Building 10/11N248 MSC 1960, Bethesda, Maryland 20892-1960, USA. Phone: 301.402.7684; Email: smh@nih.gov.
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1Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases (NIAID), NIH, Bethesda, Maryland, USA.
2Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, Maryland, USA.
3Bioinformatics and Computational Biosciences Branch, Office of Cyber Infrastructure and Computational Biology, NIAID, NIH, Bethesda, Maryland, USA.
4Marsico Lung Institute and Cystic Fibrosis Research Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
5Valley Fever Center for Excellence, University of Arizona College of Medicine–Tucson, Tucson, Arizona, USA.
6Department of Respiratory and Critical Care Medicine, Laboratory of Pulmonary Immunology and Inflammation, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China.
7NIAID Collaborative Bioinformatics Resource, NIAID, NIH, Bethesda, Maryland, USA.
8Advanced Biomedical Computational Science, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Frederick, Maryland, USA.
9Department of Internal Medicine, Division of Infectious Diseases, UC Davis Health, Sacramento, California, USA.
10Department of Immunobiology, University of Arizona, Tucson, Arizona, USA.
11Department of Medicine, University of Arizona College of Medicine–Tucson, Tucson, Arizona, USA.
12Center for Biomedical Informatics and Biostatistics and
13The Center for Applied Genetics and Genomic Medicine, Department of Medicine, University of Arizona, Tucson, Arizona, USA.
14Neutrophil Monitoring Laboratory, Applied/Developmental Research Directorate, Leidos Biomedical Research, Inc, Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA.
15Laboratory for Immunopharmacology of Microbial Products, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo, Japan.
16Immunology Service, Department of Laboratory Medicine, Clinical Center and
17Laboratory of Chronic Airway Infection, Pulmonary Branch, National Heart, Lung, and Blood Institute, NIH, Bethesda, Maryland, USA.
18Department of Immunobiology, University of Arizona, Tucson, Arizona, USA.
19VA HealthCare San Diego, San Diego, California, USA.
20Division of Infectious Diseases, Departments of Pathology and Medicine, School of Medicine, University of California San Diego, La Jolla, California, USA.
21Department of Medical Microbiology and Immunology, University of California Davis, Davis, California, USA.
Address correspondence to: Steven M. Holland, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Disease, Building 10/11N248 MSC 1960, Bethesda, Maryland 20892-1960, USA. Phone: 301.402.7684; Email: smh@nih.gov.
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1Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases (NIAID), NIH, Bethesda, Maryland, USA.
2Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, Maryland, USA.
3Bioinformatics and Computational Biosciences Branch, Office of Cyber Infrastructure and Computational Biology, NIAID, NIH, Bethesda, Maryland, USA.
4Marsico Lung Institute and Cystic Fibrosis Research Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
5Valley Fever Center for Excellence, University of Arizona College of Medicine–Tucson, Tucson, Arizona, USA.
6Department of Respiratory and Critical Care Medicine, Laboratory of Pulmonary Immunology and Inflammation, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China.
7NIAID Collaborative Bioinformatics Resource, NIAID, NIH, Bethesda, Maryland, USA.
8Advanced Biomedical Computational Science, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Frederick, Maryland, USA.
9Department of Internal Medicine, Division of Infectious Diseases, UC Davis Health, Sacramento, California, USA.
10Department of Immunobiology, University of Arizona, Tucson, Arizona, USA.
11Department of Medicine, University of Arizona College of Medicine–Tucson, Tucson, Arizona, USA.
12Center for Biomedical Informatics and Biostatistics and
13The Center for Applied Genetics and Genomic Medicine, Department of Medicine, University of Arizona, Tucson, Arizona, USA.
14Neutrophil Monitoring Laboratory, Applied/Developmental Research Directorate, Leidos Biomedical Research, Inc, Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA.
15Laboratory for Immunopharmacology of Microbial Products, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo, Japan.
16Immunology Service, Department of Laboratory Medicine, Clinical Center and
17Laboratory of Chronic Airway Infection, Pulmonary Branch, National Heart, Lung, and Blood Institute, NIH, Bethesda, Maryland, USA.
18Department of Immunobiology, University of Arizona, Tucson, Arizona, USA.
19VA HealthCare San Diego, San Diego, California, USA.
20Division of Infectious Diseases, Departments of Pathology and Medicine, School of Medicine, University of California San Diego, La Jolla, California, USA.
21Department of Medical Microbiology and Immunology, University of California Davis, Davis, California, USA.
Address correspondence to: Steven M. Holland, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Disease, Building 10/11N248 MSC 1960, Bethesda, Maryland 20892-1960, USA. Phone: 301.402.7684; Email: smh@nih.gov.
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1Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases (NIAID), NIH, Bethesda, Maryland, USA.
2Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, Maryland, USA.
3Bioinformatics and Computational Biosciences Branch, Office of Cyber Infrastructure and Computational Biology, NIAID, NIH, Bethesda, Maryland, USA.
4Marsico Lung Institute and Cystic Fibrosis Research Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
5Valley Fever Center for Excellence, University of Arizona College of Medicine–Tucson, Tucson, Arizona, USA.
6Department of Respiratory and Critical Care Medicine, Laboratory of Pulmonary Immunology and Inflammation, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China.
7NIAID Collaborative Bioinformatics Resource, NIAID, NIH, Bethesda, Maryland, USA.
8Advanced Biomedical Computational Science, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Frederick, Maryland, USA.
9Department of Internal Medicine, Division of Infectious Diseases, UC Davis Health, Sacramento, California, USA.
10Department of Immunobiology, University of Arizona, Tucson, Arizona, USA.
11Department of Medicine, University of Arizona College of Medicine–Tucson, Tucson, Arizona, USA.
12Center for Biomedical Informatics and Biostatistics and
13The Center for Applied Genetics and Genomic Medicine, Department of Medicine, University of Arizona, Tucson, Arizona, USA.
14Neutrophil Monitoring Laboratory, Applied/Developmental Research Directorate, Leidos Biomedical Research, Inc, Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA.
15Laboratory for Immunopharmacology of Microbial Products, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo, Japan.
16Immunology Service, Department of Laboratory Medicine, Clinical Center and
17Laboratory of Chronic Airway Infection, Pulmonary Branch, National Heart, Lung, and Blood Institute, NIH, Bethesda, Maryland, USA.
18Department of Immunobiology, University of Arizona, Tucson, Arizona, USA.
19VA HealthCare San Diego, San Diego, California, USA.
20Division of Infectious Diseases, Departments of Pathology and Medicine, School of Medicine, University of California San Diego, La Jolla, California, USA.
21Department of Medical Microbiology and Immunology, University of California Davis, Davis, California, USA.
Address correspondence to: Steven M. Holland, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Disease, Building 10/11N248 MSC 1960, Bethesda, Maryland 20892-1960, USA. Phone: 301.402.7684; Email: smh@nih.gov.
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1Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases (NIAID), NIH, Bethesda, Maryland, USA.
2Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, Maryland, USA.
3Bioinformatics and Computational Biosciences Branch, Office of Cyber Infrastructure and Computational Biology, NIAID, NIH, Bethesda, Maryland, USA.
4Marsico Lung Institute and Cystic Fibrosis Research Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
5Valley Fever Center for Excellence, University of Arizona College of Medicine–Tucson, Tucson, Arizona, USA.
6Department of Respiratory and Critical Care Medicine, Laboratory of Pulmonary Immunology and Inflammation, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China.
7NIAID Collaborative Bioinformatics Resource, NIAID, NIH, Bethesda, Maryland, USA.
8Advanced Biomedical Computational Science, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Frederick, Maryland, USA.
9Department of Internal Medicine, Division of Infectious Diseases, UC Davis Health, Sacramento, California, USA.
10Department of Immunobiology, University of Arizona, Tucson, Arizona, USA.
11Department of Medicine, University of Arizona College of Medicine–Tucson, Tucson, Arizona, USA.
12Center for Biomedical Informatics and Biostatistics and
13The Center for Applied Genetics and Genomic Medicine, Department of Medicine, University of Arizona, Tucson, Arizona, USA.
14Neutrophil Monitoring Laboratory, Applied/Developmental Research Directorate, Leidos Biomedical Research, Inc, Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA.
15Laboratory for Immunopharmacology of Microbial Products, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo, Japan.
16Immunology Service, Department of Laboratory Medicine, Clinical Center and
17Laboratory of Chronic Airway Infection, Pulmonary Branch, National Heart, Lung, and Blood Institute, NIH, Bethesda, Maryland, USA.
18Department of Immunobiology, University of Arizona, Tucson, Arizona, USA.
19VA HealthCare San Diego, San Diego, California, USA.
20Division of Infectious Diseases, Departments of Pathology and Medicine, School of Medicine, University of California San Diego, La Jolla, California, USA.
21Department of Medical Microbiology and Immunology, University of California Davis, Davis, California, USA.
Address correspondence to: Steven M. Holland, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Disease, Building 10/11N248 MSC 1960, Bethesda, Maryland 20892-1960, USA. Phone: 301.402.7684; Email: smh@nih.gov.
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1Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases (NIAID), NIH, Bethesda, Maryland, USA.
2Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, Maryland, USA.
3Bioinformatics and Computational Biosciences Branch, Office of Cyber Infrastructure and Computational Biology, NIAID, NIH, Bethesda, Maryland, USA.
4Marsico Lung Institute and Cystic Fibrosis Research Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
5Valley Fever Center for Excellence, University of Arizona College of Medicine–Tucson, Tucson, Arizona, USA.
6Department of Respiratory and Critical Care Medicine, Laboratory of Pulmonary Immunology and Inflammation, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China.
7NIAID Collaborative Bioinformatics Resource, NIAID, NIH, Bethesda, Maryland, USA.
8Advanced Biomedical Computational Science, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Frederick, Maryland, USA.
9Department of Internal Medicine, Division of Infectious Diseases, UC Davis Health, Sacramento, California, USA.
10Department of Immunobiology, University of Arizona, Tucson, Arizona, USA.
11Department of Medicine, University of Arizona College of Medicine–Tucson, Tucson, Arizona, USA.
12Center for Biomedical Informatics and Biostatistics and
13The Center for Applied Genetics and Genomic Medicine, Department of Medicine, University of Arizona, Tucson, Arizona, USA.
14Neutrophil Monitoring Laboratory, Applied/Developmental Research Directorate, Leidos Biomedical Research, Inc, Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA.
15Laboratory for Immunopharmacology of Microbial Products, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo, Japan.
16Immunology Service, Department of Laboratory Medicine, Clinical Center and
17Laboratory of Chronic Airway Infection, Pulmonary Branch, National Heart, Lung, and Blood Institute, NIH, Bethesda, Maryland, USA.
18Department of Immunobiology, University of Arizona, Tucson, Arizona, USA.
19VA HealthCare San Diego, San Diego, California, USA.
20Division of Infectious Diseases, Departments of Pathology and Medicine, School of Medicine, University of California San Diego, La Jolla, California, USA.
21Department of Medical Microbiology and Immunology, University of California Davis, Davis, California, USA.
Address correspondence to: Steven M. Holland, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Disease, Building 10/11N248 MSC 1960, Bethesda, Maryland 20892-1960, USA. Phone: 301.402.7684; Email: smh@nih.gov.
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1Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases (NIAID), NIH, Bethesda, Maryland, USA.
2Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, Maryland, USA.
3Bioinformatics and Computational Biosciences Branch, Office of Cyber Infrastructure and Computational Biology, NIAID, NIH, Bethesda, Maryland, USA.
4Marsico Lung Institute and Cystic Fibrosis Research Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
5Valley Fever Center for Excellence, University of Arizona College of Medicine–Tucson, Tucson, Arizona, USA.
6Department of Respiratory and Critical Care Medicine, Laboratory of Pulmonary Immunology and Inflammation, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China.
7NIAID Collaborative Bioinformatics Resource, NIAID, NIH, Bethesda, Maryland, USA.
8Advanced Biomedical Computational Science, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Frederick, Maryland, USA.
9Department of Internal Medicine, Division of Infectious Diseases, UC Davis Health, Sacramento, California, USA.
10Department of Immunobiology, University of Arizona, Tucson, Arizona, USA.
11Department of Medicine, University of Arizona College of Medicine–Tucson, Tucson, Arizona, USA.
12Center for Biomedical Informatics and Biostatistics and
13The Center for Applied Genetics and Genomic Medicine, Department of Medicine, University of Arizona, Tucson, Arizona, USA.
14Neutrophil Monitoring Laboratory, Applied/Developmental Research Directorate, Leidos Biomedical Research, Inc, Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA.
15Laboratory for Immunopharmacology of Microbial Products, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo, Japan.
16Immunology Service, Department of Laboratory Medicine, Clinical Center and
17Laboratory of Chronic Airway Infection, Pulmonary Branch, National Heart, Lung, and Blood Institute, NIH, Bethesda, Maryland, USA.
18Department of Immunobiology, University of Arizona, Tucson, Arizona, USA.
19VA HealthCare San Diego, San Diego, California, USA.
20Division of Infectious Diseases, Departments of Pathology and Medicine, School of Medicine, University of California San Diego, La Jolla, California, USA.
21Department of Medical Microbiology and Immunology, University of California Davis, Davis, California, USA.
Address correspondence to: Steven M. Holland, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Disease, Building 10/11N248 MSC 1960, Bethesda, Maryland 20892-1960, USA. Phone: 301.402.7684; Email: smh@nih.gov.
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1Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases (NIAID), NIH, Bethesda, Maryland, USA.
2Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, Maryland, USA.
3Bioinformatics and Computational Biosciences Branch, Office of Cyber Infrastructure and Computational Biology, NIAID, NIH, Bethesda, Maryland, USA.
4Marsico Lung Institute and Cystic Fibrosis Research Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
5Valley Fever Center for Excellence, University of Arizona College of Medicine–Tucson, Tucson, Arizona, USA.
6Department of Respiratory and Critical Care Medicine, Laboratory of Pulmonary Immunology and Inflammation, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China.
7NIAID Collaborative Bioinformatics Resource, NIAID, NIH, Bethesda, Maryland, USA.
8Advanced Biomedical Computational Science, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Frederick, Maryland, USA.
9Department of Internal Medicine, Division of Infectious Diseases, UC Davis Health, Sacramento, California, USA.
10Department of Immunobiology, University of Arizona, Tucson, Arizona, USA.
11Department of Medicine, University of Arizona College of Medicine–Tucson, Tucson, Arizona, USA.
12Center for Biomedical Informatics and Biostatistics and
13The Center for Applied Genetics and Genomic Medicine, Department of Medicine, University of Arizona, Tucson, Arizona, USA.
14Neutrophil Monitoring Laboratory, Applied/Developmental Research Directorate, Leidos Biomedical Research, Inc, Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA.
15Laboratory for Immunopharmacology of Microbial Products, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo, Japan.
16Immunology Service, Department of Laboratory Medicine, Clinical Center and
17Laboratory of Chronic Airway Infection, Pulmonary Branch, National Heart, Lung, and Blood Institute, NIH, Bethesda, Maryland, USA.
18Department of Immunobiology, University of Arizona, Tucson, Arizona, USA.
19VA HealthCare San Diego, San Diego, California, USA.
20Division of Infectious Diseases, Departments of Pathology and Medicine, School of Medicine, University of California San Diego, La Jolla, California, USA.
21Department of Medical Microbiology and Immunology, University of California Davis, Davis, California, USA.
Address correspondence to: Steven M. Holland, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Disease, Building 10/11N248 MSC 1960, Bethesda, Maryland 20892-1960, USA. Phone: 301.402.7684; Email: smh@nih.gov.
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1Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases (NIAID), NIH, Bethesda, Maryland, USA.
2Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, Maryland, USA.
3Bioinformatics and Computational Biosciences Branch, Office of Cyber Infrastructure and Computational Biology, NIAID, NIH, Bethesda, Maryland, USA.
4Marsico Lung Institute and Cystic Fibrosis Research Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
5Valley Fever Center for Excellence, University of Arizona College of Medicine–Tucson, Tucson, Arizona, USA.
6Department of Respiratory and Critical Care Medicine, Laboratory of Pulmonary Immunology and Inflammation, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China.
7NIAID Collaborative Bioinformatics Resource, NIAID, NIH, Bethesda, Maryland, USA.
8Advanced Biomedical Computational Science, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Frederick, Maryland, USA.
9Department of Internal Medicine, Division of Infectious Diseases, UC Davis Health, Sacramento, California, USA.
10Department of Immunobiology, University of Arizona, Tucson, Arizona, USA.
11Department of Medicine, University of Arizona College of Medicine–Tucson, Tucson, Arizona, USA.
12Center for Biomedical Informatics and Biostatistics and
13The Center for Applied Genetics and Genomic Medicine, Department of Medicine, University of Arizona, Tucson, Arizona, USA.
14Neutrophil Monitoring Laboratory, Applied/Developmental Research Directorate, Leidos Biomedical Research, Inc, Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA.
15Laboratory for Immunopharmacology of Microbial Products, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo, Japan.
16Immunology Service, Department of Laboratory Medicine, Clinical Center and
17Laboratory of Chronic Airway Infection, Pulmonary Branch, National Heart, Lung, and Blood Institute, NIH, Bethesda, Maryland, USA.
18Department of Immunobiology, University of Arizona, Tucson, Arizona, USA.
19VA HealthCare San Diego, San Diego, California, USA.
20Division of Infectious Diseases, Departments of Pathology and Medicine, School of Medicine, University of California San Diego, La Jolla, California, USA.
21Department of Medical Microbiology and Immunology, University of California Davis, Davis, California, USA.
Address correspondence to: Steven M. Holland, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Disease, Building 10/11N248 MSC 1960, Bethesda, Maryland 20892-1960, USA. Phone: 301.402.7684; Email: smh@nih.gov.
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1Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases (NIAID), NIH, Bethesda, Maryland, USA.
2Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, Maryland, USA.
3Bioinformatics and Computational Biosciences Branch, Office of Cyber Infrastructure and Computational Biology, NIAID, NIH, Bethesda, Maryland, USA.
4Marsico Lung Institute and Cystic Fibrosis Research Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
5Valley Fever Center for Excellence, University of Arizona College of Medicine–Tucson, Tucson, Arizona, USA.
6Department of Respiratory and Critical Care Medicine, Laboratory of Pulmonary Immunology and Inflammation, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China.
7NIAID Collaborative Bioinformatics Resource, NIAID, NIH, Bethesda, Maryland, USA.
8Advanced Biomedical Computational Science, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Frederick, Maryland, USA.
9Department of Internal Medicine, Division of Infectious Diseases, UC Davis Health, Sacramento, California, USA.
10Department of Immunobiology, University of Arizona, Tucson, Arizona, USA.
11Department of Medicine, University of Arizona College of Medicine–Tucson, Tucson, Arizona, USA.
12Center for Biomedical Informatics and Biostatistics and
13The Center for Applied Genetics and Genomic Medicine, Department of Medicine, University of Arizona, Tucson, Arizona, USA.
14Neutrophil Monitoring Laboratory, Applied/Developmental Research Directorate, Leidos Biomedical Research, Inc, Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA.
15Laboratory for Immunopharmacology of Microbial Products, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo, Japan.
16Immunology Service, Department of Laboratory Medicine, Clinical Center and
17Laboratory of Chronic Airway Infection, Pulmonary Branch, National Heart, Lung, and Blood Institute, NIH, Bethesda, Maryland, USA.
18Department of Immunobiology, University of Arizona, Tucson, Arizona, USA.
19VA HealthCare San Diego, San Diego, California, USA.
20Division of Infectious Diseases, Departments of Pathology and Medicine, School of Medicine, University of California San Diego, La Jolla, California, USA.
21Department of Medical Microbiology and Immunology, University of California Davis, Davis, California, USA.
Address correspondence to: Steven M. Holland, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Disease, Building 10/11N248 MSC 1960, Bethesda, Maryland 20892-1960, USA. Phone: 301.402.7684; Email: smh@nih.gov.
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1Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases (NIAID), NIH, Bethesda, Maryland, USA.
2Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, Maryland, USA.
3Bioinformatics and Computational Biosciences Branch, Office of Cyber Infrastructure and Computational Biology, NIAID, NIH, Bethesda, Maryland, USA.
4Marsico Lung Institute and Cystic Fibrosis Research Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
5Valley Fever Center for Excellence, University of Arizona College of Medicine–Tucson, Tucson, Arizona, USA.
6Department of Respiratory and Critical Care Medicine, Laboratory of Pulmonary Immunology and Inflammation, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China.
7NIAID Collaborative Bioinformatics Resource, NIAID, NIH, Bethesda, Maryland, USA.
8Advanced Biomedical Computational Science, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Frederick, Maryland, USA.
9Department of Internal Medicine, Division of Infectious Diseases, UC Davis Health, Sacramento, California, USA.
10Department of Immunobiology, University of Arizona, Tucson, Arizona, USA.
11Department of Medicine, University of Arizona College of Medicine–Tucson, Tucson, Arizona, USA.
12Center for Biomedical Informatics and Biostatistics and
13The Center for Applied Genetics and Genomic Medicine, Department of Medicine, University of Arizona, Tucson, Arizona, USA.
14Neutrophil Monitoring Laboratory, Applied/Developmental Research Directorate, Leidos Biomedical Research, Inc, Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA.
15Laboratory for Immunopharmacology of Microbial Products, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo, Japan.
16Immunology Service, Department of Laboratory Medicine, Clinical Center and
17Laboratory of Chronic Airway Infection, Pulmonary Branch, National Heart, Lung, and Blood Institute, NIH, Bethesda, Maryland, USA.
18Department of Immunobiology, University of Arizona, Tucson, Arizona, USA.
19VA HealthCare San Diego, San Diego, California, USA.
20Division of Infectious Diseases, Departments of Pathology and Medicine, School of Medicine, University of California San Diego, La Jolla, California, USA.
21Department of Medical Microbiology and Immunology, University of California Davis, Davis, California, USA.
Address correspondence to: Steven M. Holland, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Disease, Building 10/11N248 MSC 1960, Bethesda, Maryland 20892-1960, USA. Phone: 301.402.7684; Email: smh@nih.gov.
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1Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases (NIAID), NIH, Bethesda, Maryland, USA.
2Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, Maryland, USA.
3Bioinformatics and Computational Biosciences Branch, Office of Cyber Infrastructure and Computational Biology, NIAID, NIH, Bethesda, Maryland, USA.
4Marsico Lung Institute and Cystic Fibrosis Research Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
5Valley Fever Center for Excellence, University of Arizona College of Medicine–Tucson, Tucson, Arizona, USA.
6Department of Respiratory and Critical Care Medicine, Laboratory of Pulmonary Immunology and Inflammation, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China.
7NIAID Collaborative Bioinformatics Resource, NIAID, NIH, Bethesda, Maryland, USA.
8Advanced Biomedical Computational Science, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Frederick, Maryland, USA.
9Department of Internal Medicine, Division of Infectious Diseases, UC Davis Health, Sacramento, California, USA.
10Department of Immunobiology, University of Arizona, Tucson, Arizona, USA.
11Department of Medicine, University of Arizona College of Medicine–Tucson, Tucson, Arizona, USA.
12Center for Biomedical Informatics and Biostatistics and
13The Center for Applied Genetics and Genomic Medicine, Department of Medicine, University of Arizona, Tucson, Arizona, USA.
14Neutrophil Monitoring Laboratory, Applied/Developmental Research Directorate, Leidos Biomedical Research, Inc, Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA.
15Laboratory for Immunopharmacology of Microbial Products, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo, Japan.
16Immunology Service, Department of Laboratory Medicine, Clinical Center and
17Laboratory of Chronic Airway Infection, Pulmonary Branch, National Heart, Lung, and Blood Institute, NIH, Bethesda, Maryland, USA.
18Department of Immunobiology, University of Arizona, Tucson, Arizona, USA.
19VA HealthCare San Diego, San Diego, California, USA.
20Division of Infectious Diseases, Departments of Pathology and Medicine, School of Medicine, University of California San Diego, La Jolla, California, USA.
21Department of Medical Microbiology and Immunology, University of California Davis, Davis, California, USA.
Address correspondence to: Steven M. Holland, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Disease, Building 10/11N248 MSC 1960, Bethesda, Maryland 20892-1960, USA. Phone: 301.402.7684; Email: smh@nih.gov.
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Sun, L.
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1Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases (NIAID), NIH, Bethesda, Maryland, USA.
2Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, Maryland, USA.
3Bioinformatics and Computational Biosciences Branch, Office of Cyber Infrastructure and Computational Biology, NIAID, NIH, Bethesda, Maryland, USA.
4Marsico Lung Institute and Cystic Fibrosis Research Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
5Valley Fever Center for Excellence, University of Arizona College of Medicine–Tucson, Tucson, Arizona, USA.
6Department of Respiratory and Critical Care Medicine, Laboratory of Pulmonary Immunology and Inflammation, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China.
7NIAID Collaborative Bioinformatics Resource, NIAID, NIH, Bethesda, Maryland, USA.
8Advanced Biomedical Computational Science, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Frederick, Maryland, USA.
9Department of Internal Medicine, Division of Infectious Diseases, UC Davis Health, Sacramento, California, USA.
10Department of Immunobiology, University of Arizona, Tucson, Arizona, USA.
11Department of Medicine, University of Arizona College of Medicine–Tucson, Tucson, Arizona, USA.
12Center for Biomedical Informatics and Biostatistics and
13The Center for Applied Genetics and Genomic Medicine, Department of Medicine, University of Arizona, Tucson, Arizona, USA.
14Neutrophil Monitoring Laboratory, Applied/Developmental Research Directorate, Leidos Biomedical Research, Inc, Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA.
15Laboratory for Immunopharmacology of Microbial Products, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo, Japan.
16Immunology Service, Department of Laboratory Medicine, Clinical Center and
17Laboratory of Chronic Airway Infection, Pulmonary Branch, National Heart, Lung, and Blood Institute, NIH, Bethesda, Maryland, USA.
18Department of Immunobiology, University of Arizona, Tucson, Arizona, USA.
19VA HealthCare San Diego, San Diego, California, USA.
20Division of Infectious Diseases, Departments of Pathology and Medicine, School of Medicine, University of California San Diego, La Jolla, California, USA.
21Department of Medical Microbiology and Immunology, University of California Davis, Davis, California, USA.
Address correspondence to: Steven M. Holland, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Disease, Building 10/11N248 MSC 1960, Bethesda, Maryland 20892-1960, USA. Phone: 301.402.7684; Email: smh@nih.gov.
Find articles by Lack, J. in: JCI | PubMed | Google Scholar
1Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases (NIAID), NIH, Bethesda, Maryland, USA.
2Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, Maryland, USA.
3Bioinformatics and Computational Biosciences Branch, Office of Cyber Infrastructure and Computational Biology, NIAID, NIH, Bethesda, Maryland, USA.
4Marsico Lung Institute and Cystic Fibrosis Research Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
5Valley Fever Center for Excellence, University of Arizona College of Medicine–Tucson, Tucson, Arizona, USA.
6Department of Respiratory and Critical Care Medicine, Laboratory of Pulmonary Immunology and Inflammation, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China.
7NIAID Collaborative Bioinformatics Resource, NIAID, NIH, Bethesda, Maryland, USA.
8Advanced Biomedical Computational Science, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Frederick, Maryland, USA.
9Department of Internal Medicine, Division of Infectious Diseases, UC Davis Health, Sacramento, California, USA.
10Department of Immunobiology, University of Arizona, Tucson, Arizona, USA.
11Department of Medicine, University of Arizona College of Medicine–Tucson, Tucson, Arizona, USA.
12Center for Biomedical Informatics and Biostatistics and
13The Center for Applied Genetics and Genomic Medicine, Department of Medicine, University of Arizona, Tucson, Arizona, USA.
14Neutrophil Monitoring Laboratory, Applied/Developmental Research Directorate, Leidos Biomedical Research, Inc, Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA.
15Laboratory for Immunopharmacology of Microbial Products, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo, Japan.
16Immunology Service, Department of Laboratory Medicine, Clinical Center and
17Laboratory of Chronic Airway Infection, Pulmonary Branch, National Heart, Lung, and Blood Institute, NIH, Bethesda, Maryland, USA.
18Department of Immunobiology, University of Arizona, Tucson, Arizona, USA.
19VA HealthCare San Diego, San Diego, California, USA.
20Division of Infectious Diseases, Departments of Pathology and Medicine, School of Medicine, University of California San Diego, La Jolla, California, USA.
21Department of Medical Microbiology and Immunology, University of California Davis, Davis, California, USA.
Address correspondence to: Steven M. Holland, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Disease, Building 10/11N248 MSC 1960, Bethesda, Maryland 20892-1960, USA. Phone: 301.402.7684; Email: smh@nih.gov.
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Bays, D.
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1Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases (NIAID), NIH, Bethesda, Maryland, USA.
2Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, Maryland, USA.
3Bioinformatics and Computational Biosciences Branch, Office of Cyber Infrastructure and Computational Biology, NIAID, NIH, Bethesda, Maryland, USA.
4Marsico Lung Institute and Cystic Fibrosis Research Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
5Valley Fever Center for Excellence, University of Arizona College of Medicine–Tucson, Tucson, Arizona, USA.
6Department of Respiratory and Critical Care Medicine, Laboratory of Pulmonary Immunology and Inflammation, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China.
7NIAID Collaborative Bioinformatics Resource, NIAID, NIH, Bethesda, Maryland, USA.
8Advanced Biomedical Computational Science, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Frederick, Maryland, USA.
9Department of Internal Medicine, Division of Infectious Diseases, UC Davis Health, Sacramento, California, USA.
10Department of Immunobiology, University of Arizona, Tucson, Arizona, USA.
11Department of Medicine, University of Arizona College of Medicine–Tucson, Tucson, Arizona, USA.
12Center for Biomedical Informatics and Biostatistics and
13The Center for Applied Genetics and Genomic Medicine, Department of Medicine, University of Arizona, Tucson, Arizona, USA.
14Neutrophil Monitoring Laboratory, Applied/Developmental Research Directorate, Leidos Biomedical Research, Inc, Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA.
15Laboratory for Immunopharmacology of Microbial Products, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo, Japan.
16Immunology Service, Department of Laboratory Medicine, Clinical Center and
17Laboratory of Chronic Airway Infection, Pulmonary Branch, National Heart, Lung, and Blood Institute, NIH, Bethesda, Maryland, USA.
18Department of Immunobiology, University of Arizona, Tucson, Arizona, USA.
19VA HealthCare San Diego, San Diego, California, USA.
20Division of Infectious Diseases, Departments of Pathology and Medicine, School of Medicine, University of California San Diego, La Jolla, California, USA.
21Department of Medical Microbiology and Immunology, University of California Davis, Davis, California, USA.
Address correspondence to: Steven M. Holland, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Disease, Building 10/11N248 MSC 1960, Bethesda, Maryland 20892-1960, USA. Phone: 301.402.7684; Email: smh@nih.gov.
Find articles by Stewart, E. in: JCI | PubMed | Google Scholar
1Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases (NIAID), NIH, Bethesda, Maryland, USA.
2Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, Maryland, USA.
3Bioinformatics and Computational Biosciences Branch, Office of Cyber Infrastructure and Computational Biology, NIAID, NIH, Bethesda, Maryland, USA.
4Marsico Lung Institute and Cystic Fibrosis Research Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
5Valley Fever Center for Excellence, University of Arizona College of Medicine–Tucson, Tucson, Arizona, USA.
6Department of Respiratory and Critical Care Medicine, Laboratory of Pulmonary Immunology and Inflammation, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China.
7NIAID Collaborative Bioinformatics Resource, NIAID, NIH, Bethesda, Maryland, USA.
8Advanced Biomedical Computational Science, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Frederick, Maryland, USA.
9Department of Internal Medicine, Division of Infectious Diseases, UC Davis Health, Sacramento, California, USA.
10Department of Immunobiology, University of Arizona, Tucson, Arizona, USA.
11Department of Medicine, University of Arizona College of Medicine–Tucson, Tucson, Arizona, USA.
12Center for Biomedical Informatics and Biostatistics and
13The Center for Applied Genetics and Genomic Medicine, Department of Medicine, University of Arizona, Tucson, Arizona, USA.
14Neutrophil Monitoring Laboratory, Applied/Developmental Research Directorate, Leidos Biomedical Research, Inc, Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA.
15Laboratory for Immunopharmacology of Microbial Products, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo, Japan.
16Immunology Service, Department of Laboratory Medicine, Clinical Center and
17Laboratory of Chronic Airway Infection, Pulmonary Branch, National Heart, Lung, and Blood Institute, NIH, Bethesda, Maryland, USA.
18Department of Immunobiology, University of Arizona, Tucson, Arizona, USA.
19VA HealthCare San Diego, San Diego, California, USA.
20Division of Infectious Diseases, Departments of Pathology and Medicine, School of Medicine, University of California San Diego, La Jolla, California, USA.
21Department of Medical Microbiology and Immunology, University of California Davis, Davis, California, USA.
Address correspondence to: Steven M. Holland, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Disease, Building 10/11N248 MSC 1960, Bethesda, Maryland 20892-1960, USA. Phone: 301.402.7684; Email: smh@nih.gov.
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Waldman, S.
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1Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases (NIAID), NIH, Bethesda, Maryland, USA.
2Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, Maryland, USA.
3Bioinformatics and Computational Biosciences Branch, Office of Cyber Infrastructure and Computational Biology, NIAID, NIH, Bethesda, Maryland, USA.
4Marsico Lung Institute and Cystic Fibrosis Research Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
5Valley Fever Center for Excellence, University of Arizona College of Medicine–Tucson, Tucson, Arizona, USA.
6Department of Respiratory and Critical Care Medicine, Laboratory of Pulmonary Immunology and Inflammation, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China.
7NIAID Collaborative Bioinformatics Resource, NIAID, NIH, Bethesda, Maryland, USA.
8Advanced Biomedical Computational Science, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Frederick, Maryland, USA.
9Department of Internal Medicine, Division of Infectious Diseases, UC Davis Health, Sacramento, California, USA.
10Department of Immunobiology, University of Arizona, Tucson, Arizona, USA.
11Department of Medicine, University of Arizona College of Medicine–Tucson, Tucson, Arizona, USA.
12Center for Biomedical Informatics and Biostatistics and
13The Center for Applied Genetics and Genomic Medicine, Department of Medicine, University of Arizona, Tucson, Arizona, USA.
14Neutrophil Monitoring Laboratory, Applied/Developmental Research Directorate, Leidos Biomedical Research, Inc, Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA.
15Laboratory for Immunopharmacology of Microbial Products, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo, Japan.
16Immunology Service, Department of Laboratory Medicine, Clinical Center and
17Laboratory of Chronic Airway Infection, Pulmonary Branch, National Heart, Lung, and Blood Institute, NIH, Bethesda, Maryland, USA.
18Department of Immunobiology, University of Arizona, Tucson, Arizona, USA.
19VA HealthCare San Diego, San Diego, California, USA.
20Division of Infectious Diseases, Departments of Pathology and Medicine, School of Medicine, University of California San Diego, La Jolla, California, USA.
21Department of Medical Microbiology and Immunology, University of California Davis, Davis, California, USA.
Address correspondence to: Steven M. Holland, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Disease, Building 10/11N248 MSC 1960, Bethesda, Maryland 20892-1960, USA. Phone: 301.402.7684; Email: smh@nih.gov.
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Powell, D.
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1Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases (NIAID), NIH, Bethesda, Maryland, USA.
2Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, Maryland, USA.
3Bioinformatics and Computational Biosciences Branch, Office of Cyber Infrastructure and Computational Biology, NIAID, NIH, Bethesda, Maryland, USA.
4Marsico Lung Institute and Cystic Fibrosis Research Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
5Valley Fever Center for Excellence, University of Arizona College of Medicine–Tucson, Tucson, Arizona, USA.
6Department of Respiratory and Critical Care Medicine, Laboratory of Pulmonary Immunology and Inflammation, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China.
7NIAID Collaborative Bioinformatics Resource, NIAID, NIH, Bethesda, Maryland, USA.
8Advanced Biomedical Computational Science, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Frederick, Maryland, USA.
9Department of Internal Medicine, Division of Infectious Diseases, UC Davis Health, Sacramento, California, USA.
10Department of Immunobiology, University of Arizona, Tucson, Arizona, USA.
11Department of Medicine, University of Arizona College of Medicine–Tucson, Tucson, Arizona, USA.
12Center for Biomedical Informatics and Biostatistics and
13The Center for Applied Genetics and Genomic Medicine, Department of Medicine, University of Arizona, Tucson, Arizona, USA.
14Neutrophil Monitoring Laboratory, Applied/Developmental Research Directorate, Leidos Biomedical Research, Inc, Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA.
15Laboratory for Immunopharmacology of Microbial Products, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo, Japan.
16Immunology Service, Department of Laboratory Medicine, Clinical Center and
17Laboratory of Chronic Airway Infection, Pulmonary Branch, National Heart, Lung, and Blood Institute, NIH, Bethesda, Maryland, USA.
18Department of Immunobiology, University of Arizona, Tucson, Arizona, USA.
19VA HealthCare San Diego, San Diego, California, USA.
20Division of Infectious Diseases, Departments of Pathology and Medicine, School of Medicine, University of California San Diego, La Jolla, California, USA.
21Department of Medical Microbiology and Immunology, University of California Davis, Davis, California, USA.
Address correspondence to: Steven M. Holland, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Disease, Building 10/11N248 MSC 1960, Bethesda, Maryland 20892-1960, USA. Phone: 301.402.7684; Email: smh@nih.gov.
Find articles by Donovan, F. in: JCI | PubMed | Google Scholar
1Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases (NIAID), NIH, Bethesda, Maryland, USA.
2Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, Maryland, USA.
3Bioinformatics and Computational Biosciences Branch, Office of Cyber Infrastructure and Computational Biology, NIAID, NIH, Bethesda, Maryland, USA.
4Marsico Lung Institute and Cystic Fibrosis Research Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
5Valley Fever Center for Excellence, University of Arizona College of Medicine–Tucson, Tucson, Arizona, USA.
6Department of Respiratory and Critical Care Medicine, Laboratory of Pulmonary Immunology and Inflammation, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China.
7NIAID Collaborative Bioinformatics Resource, NIAID, NIH, Bethesda, Maryland, USA.
8Advanced Biomedical Computational Science, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Frederick, Maryland, USA.
9Department of Internal Medicine, Division of Infectious Diseases, UC Davis Health, Sacramento, California, USA.
10Department of Immunobiology, University of Arizona, Tucson, Arizona, USA.
11Department of Medicine, University of Arizona College of Medicine–Tucson, Tucson, Arizona, USA.
12Center for Biomedical Informatics and Biostatistics and
13The Center for Applied Genetics and Genomic Medicine, Department of Medicine, University of Arizona, Tucson, Arizona, USA.
14Neutrophil Monitoring Laboratory, Applied/Developmental Research Directorate, Leidos Biomedical Research, Inc, Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA.
15Laboratory for Immunopharmacology of Microbial Products, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo, Japan.
16Immunology Service, Department of Laboratory Medicine, Clinical Center and
17Laboratory of Chronic Airway Infection, Pulmonary Branch, National Heart, Lung, and Blood Institute, NIH, Bethesda, Maryland, USA.
18Department of Immunobiology, University of Arizona, Tucson, Arizona, USA.
19VA HealthCare San Diego, San Diego, California, USA.
20Division of Infectious Diseases, Departments of Pathology and Medicine, School of Medicine, University of California San Diego, La Jolla, California, USA.
21Department of Medical Microbiology and Immunology, University of California Davis, Davis, California, USA.
Address correspondence to: Steven M. Holland, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Disease, Building 10/11N248 MSC 1960, Bethesda, Maryland 20892-1960, USA. Phone: 301.402.7684; Email: smh@nih.gov.
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Desai, J.
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1Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases (NIAID), NIH, Bethesda, Maryland, USA.
2Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, Maryland, USA.
3Bioinformatics and Computational Biosciences Branch, Office of Cyber Infrastructure and Computational Biology, NIAID, NIH, Bethesda, Maryland, USA.
4Marsico Lung Institute and Cystic Fibrosis Research Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
5Valley Fever Center for Excellence, University of Arizona College of Medicine–Tucson, Tucson, Arizona, USA.
6Department of Respiratory and Critical Care Medicine, Laboratory of Pulmonary Immunology and Inflammation, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China.
7NIAID Collaborative Bioinformatics Resource, NIAID, NIH, Bethesda, Maryland, USA.
8Advanced Biomedical Computational Science, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Frederick, Maryland, USA.
9Department of Internal Medicine, Division of Infectious Diseases, UC Davis Health, Sacramento, California, USA.
10Department of Immunobiology, University of Arizona, Tucson, Arizona, USA.
11Department of Medicine, University of Arizona College of Medicine–Tucson, Tucson, Arizona, USA.
12Center for Biomedical Informatics and Biostatistics and
13The Center for Applied Genetics and Genomic Medicine, Department of Medicine, University of Arizona, Tucson, Arizona, USA.
14Neutrophil Monitoring Laboratory, Applied/Developmental Research Directorate, Leidos Biomedical Research, Inc, Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA.
15Laboratory for Immunopharmacology of Microbial Products, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo, Japan.
16Immunology Service, Department of Laboratory Medicine, Clinical Center and
17Laboratory of Chronic Airway Infection, Pulmonary Branch, National Heart, Lung, and Blood Institute, NIH, Bethesda, Maryland, USA.
18Department of Immunobiology, University of Arizona, Tucson, Arizona, USA.
19VA HealthCare San Diego, San Diego, California, USA.
20Division of Infectious Diseases, Departments of Pathology and Medicine, School of Medicine, University of California San Diego, La Jolla, California, USA.
21Department of Medical Microbiology and Immunology, University of California Davis, Davis, California, USA.
Address correspondence to: Steven M. Holland, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Disease, Building 10/11N248 MSC 1960, Bethesda, Maryland 20892-1960, USA. Phone: 301.402.7684; Email: smh@nih.gov.
Find articles by Pouladi, N. in: JCI | PubMed | Google Scholar
1Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases (NIAID), NIH, Bethesda, Maryland, USA.
2Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, Maryland, USA.
3Bioinformatics and Computational Biosciences Branch, Office of Cyber Infrastructure and Computational Biology, NIAID, NIH, Bethesda, Maryland, USA.
4Marsico Lung Institute and Cystic Fibrosis Research Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
5Valley Fever Center for Excellence, University of Arizona College of Medicine–Tucson, Tucson, Arizona, USA.
6Department of Respiratory and Critical Care Medicine, Laboratory of Pulmonary Immunology and Inflammation, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China.
7NIAID Collaborative Bioinformatics Resource, NIAID, NIH, Bethesda, Maryland, USA.
8Advanced Biomedical Computational Science, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Frederick, Maryland, USA.
9Department of Internal Medicine, Division of Infectious Diseases, UC Davis Health, Sacramento, California, USA.
10Department of Immunobiology, University of Arizona, Tucson, Arizona, USA.
11Department of Medicine, University of Arizona College of Medicine–Tucson, Tucson, Arizona, USA.
12Center for Biomedical Informatics and Biostatistics and
13The Center for Applied Genetics and Genomic Medicine, Department of Medicine, University of Arizona, Tucson, Arizona, USA.
14Neutrophil Monitoring Laboratory, Applied/Developmental Research Directorate, Leidos Biomedical Research, Inc, Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA.
15Laboratory for Immunopharmacology of Microbial Products, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo, Japan.
16Immunology Service, Department of Laboratory Medicine, Clinical Center and
17Laboratory of Chronic Airway Infection, Pulmonary Branch, National Heart, Lung, and Blood Institute, NIH, Bethesda, Maryland, USA.
18Department of Immunobiology, University of Arizona, Tucson, Arizona, USA.
19VA HealthCare San Diego, San Diego, California, USA.
20Division of Infectious Diseases, Departments of Pathology and Medicine, School of Medicine, University of California San Diego, La Jolla, California, USA.
21Department of Medical Microbiology and Immunology, University of California Davis, Davis, California, USA.
Address correspondence to: Steven M. Holland, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Disease, Building 10/11N248 MSC 1960, Bethesda, Maryland 20892-1960, USA. Phone: 301.402.7684; Email: smh@nih.gov.
Find articles by Long Priel, D. in: JCI | PubMed | Google Scholar
1Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases (NIAID), NIH, Bethesda, Maryland, USA.
2Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, Maryland, USA.
3Bioinformatics and Computational Biosciences Branch, Office of Cyber Infrastructure and Computational Biology, NIAID, NIH, Bethesda, Maryland, USA.
4Marsico Lung Institute and Cystic Fibrosis Research Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
5Valley Fever Center for Excellence, University of Arizona College of Medicine–Tucson, Tucson, Arizona, USA.
6Department of Respiratory and Critical Care Medicine, Laboratory of Pulmonary Immunology and Inflammation, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China.
7NIAID Collaborative Bioinformatics Resource, NIAID, NIH, Bethesda, Maryland, USA.
8Advanced Biomedical Computational Science, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Frederick, Maryland, USA.
9Department of Internal Medicine, Division of Infectious Diseases, UC Davis Health, Sacramento, California, USA.
10Department of Immunobiology, University of Arizona, Tucson, Arizona, USA.
11Department of Medicine, University of Arizona College of Medicine–Tucson, Tucson, Arizona, USA.
12Center for Biomedical Informatics and Biostatistics and
13The Center for Applied Genetics and Genomic Medicine, Department of Medicine, University of Arizona, Tucson, Arizona, USA.
14Neutrophil Monitoring Laboratory, Applied/Developmental Research Directorate, Leidos Biomedical Research, Inc, Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA.
15Laboratory for Immunopharmacology of Microbial Products, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo, Japan.
16Immunology Service, Department of Laboratory Medicine, Clinical Center and
17Laboratory of Chronic Airway Infection, Pulmonary Branch, National Heart, Lung, and Blood Institute, NIH, Bethesda, Maryland, USA.
18Department of Immunobiology, University of Arizona, Tucson, Arizona, USA.
19VA HealthCare San Diego, San Diego, California, USA.
20Division of Infectious Diseases, Departments of Pathology and Medicine, School of Medicine, University of California San Diego, La Jolla, California, USA.
21Department of Medical Microbiology and Immunology, University of California Davis, Davis, California, USA.
Address correspondence to: Steven M. Holland, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Disease, Building 10/11N248 MSC 1960, Bethesda, Maryland 20892-1960, USA. Phone: 301.402.7684; Email: smh@nih.gov.
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Yamanaka, D.
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1Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases (NIAID), NIH, Bethesda, Maryland, USA.
2Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, Maryland, USA.
3Bioinformatics and Computational Biosciences Branch, Office of Cyber Infrastructure and Computational Biology, NIAID, NIH, Bethesda, Maryland, USA.
4Marsico Lung Institute and Cystic Fibrosis Research Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
5Valley Fever Center for Excellence, University of Arizona College of Medicine–Tucson, Tucson, Arizona, USA.
6Department of Respiratory and Critical Care Medicine, Laboratory of Pulmonary Immunology and Inflammation, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China.
7NIAID Collaborative Bioinformatics Resource, NIAID, NIH, Bethesda, Maryland, USA.
8Advanced Biomedical Computational Science, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Frederick, Maryland, USA.
9Department of Internal Medicine, Division of Infectious Diseases, UC Davis Health, Sacramento, California, USA.
10Department of Immunobiology, University of Arizona, Tucson, Arizona, USA.
11Department of Medicine, University of Arizona College of Medicine–Tucson, Tucson, Arizona, USA.
12Center for Biomedical Informatics and Biostatistics and
13The Center for Applied Genetics and Genomic Medicine, Department of Medicine, University of Arizona, Tucson, Arizona, USA.
14Neutrophil Monitoring Laboratory, Applied/Developmental Research Directorate, Leidos Biomedical Research, Inc, Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA.
15Laboratory for Immunopharmacology of Microbial Products, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo, Japan.
16Immunology Service, Department of Laboratory Medicine, Clinical Center and
17Laboratory of Chronic Airway Infection, Pulmonary Branch, National Heart, Lung, and Blood Institute, NIH, Bethesda, Maryland, USA.
18Department of Immunobiology, University of Arizona, Tucson, Arizona, USA.
19VA HealthCare San Diego, San Diego, California, USA.
20Division of Infectious Diseases, Departments of Pathology and Medicine, School of Medicine, University of California San Diego, La Jolla, California, USA.
21Department of Medical Microbiology and Immunology, University of California Davis, Davis, California, USA.
Address correspondence to: Steven M. Holland, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Disease, Building 10/11N248 MSC 1960, Bethesda, Maryland 20892-1960, USA. Phone: 301.402.7684; Email: smh@nih.gov.
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Rosenzweig, S.
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1Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases (NIAID), NIH, Bethesda, Maryland, USA.
2Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, Maryland, USA.
3Bioinformatics and Computational Biosciences Branch, Office of Cyber Infrastructure and Computational Biology, NIAID, NIH, Bethesda, Maryland, USA.
4Marsico Lung Institute and Cystic Fibrosis Research Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
5Valley Fever Center for Excellence, University of Arizona College of Medicine–Tucson, Tucson, Arizona, USA.
6Department of Respiratory and Critical Care Medicine, Laboratory of Pulmonary Immunology and Inflammation, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China.
7NIAID Collaborative Bioinformatics Resource, NIAID, NIH, Bethesda, Maryland, USA.
8Advanced Biomedical Computational Science, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Frederick, Maryland, USA.
9Department of Internal Medicine, Division of Infectious Diseases, UC Davis Health, Sacramento, California, USA.
10Department of Immunobiology, University of Arizona, Tucson, Arizona, USA.
11Department of Medicine, University of Arizona College of Medicine–Tucson, Tucson, Arizona, USA.
12Center for Biomedical Informatics and Biostatistics and
13The Center for Applied Genetics and Genomic Medicine, Department of Medicine, University of Arizona, Tucson, Arizona, USA.
14Neutrophil Monitoring Laboratory, Applied/Developmental Research Directorate, Leidos Biomedical Research, Inc, Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA.
15Laboratory for Immunopharmacology of Microbial Products, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo, Japan.
16Immunology Service, Department of Laboratory Medicine, Clinical Center and
17Laboratory of Chronic Airway Infection, Pulmonary Branch, National Heart, Lung, and Blood Institute, NIH, Bethesda, Maryland, USA.
18Department of Immunobiology, University of Arizona, Tucson, Arizona, USA.
19VA HealthCare San Diego, San Diego, California, USA.
20Division of Infectious Diseases, Departments of Pathology and Medicine, School of Medicine, University of California San Diego, La Jolla, California, USA.
21Department of Medical Microbiology and Immunology, University of California Davis, Davis, California, USA.
Address correspondence to: Steven M. Holland, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Disease, Building 10/11N248 MSC 1960, Bethesda, Maryland 20892-1960, USA. Phone: 301.402.7684; Email: smh@nih.gov.
Find articles by Niemela, J. in: JCI | PubMed | Google Scholar
1Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases (NIAID), NIH, Bethesda, Maryland, USA.
2Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, Maryland, USA.
3Bioinformatics and Computational Biosciences Branch, Office of Cyber Infrastructure and Computational Biology, NIAID, NIH, Bethesda, Maryland, USA.
4Marsico Lung Institute and Cystic Fibrosis Research Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
5Valley Fever Center for Excellence, University of Arizona College of Medicine–Tucson, Tucson, Arizona, USA.
6Department of Respiratory and Critical Care Medicine, Laboratory of Pulmonary Immunology and Inflammation, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China.
7NIAID Collaborative Bioinformatics Resource, NIAID, NIH, Bethesda, Maryland, USA.
8Advanced Biomedical Computational Science, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Frederick, Maryland, USA.
9Department of Internal Medicine, Division of Infectious Diseases, UC Davis Health, Sacramento, California, USA.
10Department of Immunobiology, University of Arizona, Tucson, Arizona, USA.
11Department of Medicine, University of Arizona College of Medicine–Tucson, Tucson, Arizona, USA.
12Center for Biomedical Informatics and Biostatistics and
13The Center for Applied Genetics and Genomic Medicine, Department of Medicine, University of Arizona, Tucson, Arizona, USA.
14Neutrophil Monitoring Laboratory, Applied/Developmental Research Directorate, Leidos Biomedical Research, Inc, Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA.
15Laboratory for Immunopharmacology of Microbial Products, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo, Japan.
16Immunology Service, Department of Laboratory Medicine, Clinical Center and
17Laboratory of Chronic Airway Infection, Pulmonary Branch, National Heart, Lung, and Blood Institute, NIH, Bethesda, Maryland, USA.
18Department of Immunobiology, University of Arizona, Tucson, Arizona, USA.
19VA HealthCare San Diego, San Diego, California, USA.
20Division of Infectious Diseases, Departments of Pathology and Medicine, School of Medicine, University of California San Diego, La Jolla, California, USA.
21Department of Medical Microbiology and Immunology, University of California Davis, Davis, California, USA.
Address correspondence to: Steven M. Holland, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Disease, Building 10/11N248 MSC 1960, Bethesda, Maryland 20892-1960, USA. Phone: 301.402.7684; Email: smh@nih.gov.
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1Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases (NIAID), NIH, Bethesda, Maryland, USA.
2Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, Maryland, USA.
3Bioinformatics and Computational Biosciences Branch, Office of Cyber Infrastructure and Computational Biology, NIAID, NIH, Bethesda, Maryland, USA.
4Marsico Lung Institute and Cystic Fibrosis Research Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
5Valley Fever Center for Excellence, University of Arizona College of Medicine–Tucson, Tucson, Arizona, USA.
6Department of Respiratory and Critical Care Medicine, Laboratory of Pulmonary Immunology and Inflammation, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China.
7NIAID Collaborative Bioinformatics Resource, NIAID, NIH, Bethesda, Maryland, USA.
8Advanced Biomedical Computational Science, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Frederick, Maryland, USA.
9Department of Internal Medicine, Division of Infectious Diseases, UC Davis Health, Sacramento, California, USA.
10Department of Immunobiology, University of Arizona, Tucson, Arizona, USA.
11Department of Medicine, University of Arizona College of Medicine–Tucson, Tucson, Arizona, USA.
12Center for Biomedical Informatics and Biostatistics and
13The Center for Applied Genetics and Genomic Medicine, Department of Medicine, University of Arizona, Tucson, Arizona, USA.
14Neutrophil Monitoring Laboratory, Applied/Developmental Research Directorate, Leidos Biomedical Research, Inc, Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA.
15Laboratory for Immunopharmacology of Microbial Products, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo, Japan.
16Immunology Service, Department of Laboratory Medicine, Clinical Center and
17Laboratory of Chronic Airway Infection, Pulmonary Branch, National Heart, Lung, and Blood Institute, NIH, Bethesda, Maryland, USA.
18Department of Immunobiology, University of Arizona, Tucson, Arizona, USA.
19VA HealthCare San Diego, San Diego, California, USA.
20Division of Infectious Diseases, Departments of Pathology and Medicine, School of Medicine, University of California San Diego, La Jolla, California, USA.
21Department of Medical Microbiology and Immunology, University of California Davis, Davis, California, USA.
Address correspondence to: Steven M. Holland, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Disease, Building 10/11N248 MSC 1960, Bethesda, Maryland 20892-1960, USA. Phone: 301.402.7684; Email: smh@nih.gov.
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1Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases (NIAID), NIH, Bethesda, Maryland, USA.
2Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, Maryland, USA.
3Bioinformatics and Computational Biosciences Branch, Office of Cyber Infrastructure and Computational Biology, NIAID, NIH, Bethesda, Maryland, USA.
4Marsico Lung Institute and Cystic Fibrosis Research Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
5Valley Fever Center for Excellence, University of Arizona College of Medicine–Tucson, Tucson, Arizona, USA.
6Department of Respiratory and Critical Care Medicine, Laboratory of Pulmonary Immunology and Inflammation, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China.
7NIAID Collaborative Bioinformatics Resource, NIAID, NIH, Bethesda, Maryland, USA.
8Advanced Biomedical Computational Science, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Frederick, Maryland, USA.
9Department of Internal Medicine, Division of Infectious Diseases, UC Davis Health, Sacramento, California, USA.
10Department of Immunobiology, University of Arizona, Tucson, Arizona, USA.
11Department of Medicine, University of Arizona College of Medicine–Tucson, Tucson, Arizona, USA.
12Center for Biomedical Informatics and Biostatistics and
13The Center for Applied Genetics and Genomic Medicine, Department of Medicine, University of Arizona, Tucson, Arizona, USA.
14Neutrophil Monitoring Laboratory, Applied/Developmental Research Directorate, Leidos Biomedical Research, Inc, Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA.
15Laboratory for Immunopharmacology of Microbial Products, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo, Japan.
16Immunology Service, Department of Laboratory Medicine, Clinical Center and
17Laboratory of Chronic Airway Infection, Pulmonary Branch, National Heart, Lung, and Blood Institute, NIH, Bethesda, Maryland, USA.
18Department of Immunobiology, University of Arizona, Tucson, Arizona, USA.
19VA HealthCare San Diego, San Diego, California, USA.
20Division of Infectious Diseases, Departments of Pathology and Medicine, School of Medicine, University of California San Diego, La Jolla, California, USA.
21Department of Medical Microbiology and Immunology, University of California Davis, Davis, California, USA.
Address correspondence to: Steven M. Holland, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Disease, Building 10/11N248 MSC 1960, Bethesda, Maryland 20892-1960, USA. Phone: 301.402.7684; Email: smh@nih.gov.
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Zerbe, C.
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1Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases (NIAID), NIH, Bethesda, Maryland, USA.
2Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, Maryland, USA.
3Bioinformatics and Computational Biosciences Branch, Office of Cyber Infrastructure and Computational Biology, NIAID, NIH, Bethesda, Maryland, USA.
4Marsico Lung Institute and Cystic Fibrosis Research Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
5Valley Fever Center for Excellence, University of Arizona College of Medicine–Tucson, Tucson, Arizona, USA.
6Department of Respiratory and Critical Care Medicine, Laboratory of Pulmonary Immunology and Inflammation, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China.
7NIAID Collaborative Bioinformatics Resource, NIAID, NIH, Bethesda, Maryland, USA.
8Advanced Biomedical Computational Science, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Frederick, Maryland, USA.
9Department of Internal Medicine, Division of Infectious Diseases, UC Davis Health, Sacramento, California, USA.
10Department of Immunobiology, University of Arizona, Tucson, Arizona, USA.
11Department of Medicine, University of Arizona College of Medicine–Tucson, Tucson, Arizona, USA.
12Center for Biomedical Informatics and Biostatistics and
13The Center for Applied Genetics and Genomic Medicine, Department of Medicine, University of Arizona, Tucson, Arizona, USA.
14Neutrophil Monitoring Laboratory, Applied/Developmental Research Directorate, Leidos Biomedical Research, Inc, Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA.
15Laboratory for Immunopharmacology of Microbial Products, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo, Japan.
16Immunology Service, Department of Laboratory Medicine, Clinical Center and
17Laboratory of Chronic Airway Infection, Pulmonary Branch, National Heart, Lung, and Blood Institute, NIH, Bethesda, Maryland, USA.
18Department of Immunobiology, University of Arizona, Tucson, Arizona, USA.
19VA HealthCare San Diego, San Diego, California, USA.
20Division of Infectious Diseases, Departments of Pathology and Medicine, School of Medicine, University of California San Diego, La Jolla, California, USA.
21Department of Medical Microbiology and Immunology, University of California Davis, Davis, California, USA.
Address correspondence to: Steven M. Holland, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Disease, Building 10/11N248 MSC 1960, Bethesda, Maryland 20892-1960, USA. Phone: 301.402.7684; Email: smh@nih.gov.
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Kuhns, D.
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1Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases (NIAID), NIH, Bethesda, Maryland, USA.
2Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, Maryland, USA.
3Bioinformatics and Computational Biosciences Branch, Office of Cyber Infrastructure and Computational Biology, NIAID, NIH, Bethesda, Maryland, USA.
4Marsico Lung Institute and Cystic Fibrosis Research Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
5Valley Fever Center for Excellence, University of Arizona College of Medicine–Tucson, Tucson, Arizona, USA.
6Department of Respiratory and Critical Care Medicine, Laboratory of Pulmonary Immunology and Inflammation, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China.
7NIAID Collaborative Bioinformatics Resource, NIAID, NIH, Bethesda, Maryland, USA.
8Advanced Biomedical Computational Science, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Frederick, Maryland, USA.
9Department of Internal Medicine, Division of Infectious Diseases, UC Davis Health, Sacramento, California, USA.
10Department of Immunobiology, University of Arizona, Tucson, Arizona, USA.
11Department of Medicine, University of Arizona College of Medicine–Tucson, Tucson, Arizona, USA.
12Center for Biomedical Informatics and Biostatistics and
13The Center for Applied Genetics and Genomic Medicine, Department of Medicine, University of Arizona, Tucson, Arizona, USA.
14Neutrophil Monitoring Laboratory, Applied/Developmental Research Directorate, Leidos Biomedical Research, Inc, Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA.
15Laboratory for Immunopharmacology of Microbial Products, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo, Japan.
16Immunology Service, Department of Laboratory Medicine, Clinical Center and
17Laboratory of Chronic Airway Infection, Pulmonary Branch, National Heart, Lung, and Blood Institute, NIH, Bethesda, Maryland, USA.
18Department of Immunobiology, University of Arizona, Tucson, Arizona, USA.
19VA HealthCare San Diego, San Diego, California, USA.
20Division of Infectious Diseases, Departments of Pathology and Medicine, School of Medicine, University of California San Diego, La Jolla, California, USA.
21Department of Medical Microbiology and Immunology, University of California Davis, Davis, California, USA.
Address correspondence to: Steven M. Holland, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Disease, Building 10/11N248 MSC 1960, Bethesda, Maryland 20892-1960, USA. Phone: 301.402.7684; Email: smh@nih.gov.
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Lussier, Y.
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1Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases (NIAID), NIH, Bethesda, Maryland, USA.
2Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, Maryland, USA.
3Bioinformatics and Computational Biosciences Branch, Office of Cyber Infrastructure and Computational Biology, NIAID, NIH, Bethesda, Maryland, USA.
4Marsico Lung Institute and Cystic Fibrosis Research Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
5Valley Fever Center for Excellence, University of Arizona College of Medicine–Tucson, Tucson, Arizona, USA.
6Department of Respiratory and Critical Care Medicine, Laboratory of Pulmonary Immunology and Inflammation, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China.
7NIAID Collaborative Bioinformatics Resource, NIAID, NIH, Bethesda, Maryland, USA.
8Advanced Biomedical Computational Science, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Frederick, Maryland, USA.
9Department of Internal Medicine, Division of Infectious Diseases, UC Davis Health, Sacramento, California, USA.
10Department of Immunobiology, University of Arizona, Tucson, Arizona, USA.
11Department of Medicine, University of Arizona College of Medicine–Tucson, Tucson, Arizona, USA.
12Center for Biomedical Informatics and Biostatistics and
13The Center for Applied Genetics and Genomic Medicine, Department of Medicine, University of Arizona, Tucson, Arizona, USA.
14Neutrophil Monitoring Laboratory, Applied/Developmental Research Directorate, Leidos Biomedical Research, Inc, Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA.
15Laboratory for Immunopharmacology of Microbial Products, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo, Japan.
16Immunology Service, Department of Laboratory Medicine, Clinical Center and
17Laboratory of Chronic Airway Infection, Pulmonary Branch, National Heart, Lung, and Blood Institute, NIH, Bethesda, Maryland, USA.
18Department of Immunobiology, University of Arizona, Tucson, Arizona, USA.
19VA HealthCare San Diego, San Diego, California, USA.
20Division of Infectious Diseases, Departments of Pathology and Medicine, School of Medicine, University of California San Diego, La Jolla, California, USA.
21Department of Medical Microbiology and Immunology, University of California Davis, Davis, California, USA.
Address correspondence to: Steven M. Holland, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Disease, Building 10/11N248 MSC 1960, Bethesda, Maryland 20892-1960, USA. Phone: 301.402.7684; Email: smh@nih.gov.
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Olivier, K.
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1Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases (NIAID), NIH, Bethesda, Maryland, USA.
2Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, Maryland, USA.
3Bioinformatics and Computational Biosciences Branch, Office of Cyber Infrastructure and Computational Biology, NIAID, NIH, Bethesda, Maryland, USA.
4Marsico Lung Institute and Cystic Fibrosis Research Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
5Valley Fever Center for Excellence, University of Arizona College of Medicine–Tucson, Tucson, Arizona, USA.
6Department of Respiratory and Critical Care Medicine, Laboratory of Pulmonary Immunology and Inflammation, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China.
7NIAID Collaborative Bioinformatics Resource, NIAID, NIH, Bethesda, Maryland, USA.
8Advanced Biomedical Computational Science, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Frederick, Maryland, USA.
9Department of Internal Medicine, Division of Infectious Diseases, UC Davis Health, Sacramento, California, USA.
10Department of Immunobiology, University of Arizona, Tucson, Arizona, USA.
11Department of Medicine, University of Arizona College of Medicine–Tucson, Tucson, Arizona, USA.
12Center for Biomedical Informatics and Biostatistics and
13The Center for Applied Genetics and Genomic Medicine, Department of Medicine, University of Arizona, Tucson, Arizona, USA.
14Neutrophil Monitoring Laboratory, Applied/Developmental Research Directorate, Leidos Biomedical Research, Inc, Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA.
15Laboratory for Immunopharmacology of Microbial Products, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo, Japan.
16Immunology Service, Department of Laboratory Medicine, Clinical Center and
17Laboratory of Chronic Airway Infection, Pulmonary Branch, National Heart, Lung, and Blood Institute, NIH, Bethesda, Maryland, USA.
18Department of Immunobiology, University of Arizona, Tucson, Arizona, USA.
19VA HealthCare San Diego, San Diego, California, USA.
20Division of Infectious Diseases, Departments of Pathology and Medicine, School of Medicine, University of California San Diego, La Jolla, California, USA.
21Department of Medical Microbiology and Immunology, University of California Davis, Davis, California, USA.
Address correspondence to: Steven M. Holland, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Disease, Building 10/11N248 MSC 1960, Bethesda, Maryland 20892-1960, USA. Phone: 301.402.7684; Email: smh@nih.gov.
Find articles by Boucher, R. in: JCI | PubMed | Google Scholar
1Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases (NIAID), NIH, Bethesda, Maryland, USA.
2Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, Maryland, USA.
3Bioinformatics and Computational Biosciences Branch, Office of Cyber Infrastructure and Computational Biology, NIAID, NIH, Bethesda, Maryland, USA.
4Marsico Lung Institute and Cystic Fibrosis Research Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
5Valley Fever Center for Excellence, University of Arizona College of Medicine–Tucson, Tucson, Arizona, USA.
6Department of Respiratory and Critical Care Medicine, Laboratory of Pulmonary Immunology and Inflammation, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China.
7NIAID Collaborative Bioinformatics Resource, NIAID, NIH, Bethesda, Maryland, USA.
8Advanced Biomedical Computational Science, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Frederick, Maryland, USA.
9Department of Internal Medicine, Division of Infectious Diseases, UC Davis Health, Sacramento, California, USA.
10Department of Immunobiology, University of Arizona, Tucson, Arizona, USA.
11Department of Medicine, University of Arizona College of Medicine–Tucson, Tucson, Arizona, USA.
12Center for Biomedical Informatics and Biostatistics and
13The Center for Applied Genetics and Genomic Medicine, Department of Medicine, University of Arizona, Tucson, Arizona, USA.
14Neutrophil Monitoring Laboratory, Applied/Developmental Research Directorate, Leidos Biomedical Research, Inc, Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA.
15Laboratory for Immunopharmacology of Microbial Products, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo, Japan.
16Immunology Service, Department of Laboratory Medicine, Clinical Center and
17Laboratory of Chronic Airway Infection, Pulmonary Branch, National Heart, Lung, and Blood Institute, NIH, Bethesda, Maryland, USA.
18Department of Immunobiology, University of Arizona, Tucson, Arizona, USA.
19VA HealthCare San Diego, San Diego, California, USA.
20Division of Infectious Diseases, Departments of Pathology and Medicine, School of Medicine, University of California San Diego, La Jolla, California, USA.
21Department of Medical Microbiology and Immunology, University of California Davis, Davis, California, USA.
Address correspondence to: Steven M. Holland, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Disease, Building 10/11N248 MSC 1960, Bethesda, Maryland 20892-1960, USA. Phone: 301.402.7684; Email: smh@nih.gov.
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Hickman, H.
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1Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases (NIAID), NIH, Bethesda, Maryland, USA.
2Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, Maryland, USA.
3Bioinformatics and Computational Biosciences Branch, Office of Cyber Infrastructure and Computational Biology, NIAID, NIH, Bethesda, Maryland, USA.
4Marsico Lung Institute and Cystic Fibrosis Research Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
5Valley Fever Center for Excellence, University of Arizona College of Medicine–Tucson, Tucson, Arizona, USA.
6Department of Respiratory and Critical Care Medicine, Laboratory of Pulmonary Immunology and Inflammation, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China.
7NIAID Collaborative Bioinformatics Resource, NIAID, NIH, Bethesda, Maryland, USA.
8Advanced Biomedical Computational Science, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Frederick, Maryland, USA.
9Department of Internal Medicine, Division of Infectious Diseases, UC Davis Health, Sacramento, California, USA.
10Department of Immunobiology, University of Arizona, Tucson, Arizona, USA.
11Department of Medicine, University of Arizona College of Medicine–Tucson, Tucson, Arizona, USA.
12Center for Biomedical Informatics and Biostatistics and
13The Center for Applied Genetics and Genomic Medicine, Department of Medicine, University of Arizona, Tucson, Arizona, USA.
14Neutrophil Monitoring Laboratory, Applied/Developmental Research Directorate, Leidos Biomedical Research, Inc, Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA.
15Laboratory for Immunopharmacology of Microbial Products, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo, Japan.
16Immunology Service, Department of Laboratory Medicine, Clinical Center and
17Laboratory of Chronic Airway Infection, Pulmonary Branch, National Heart, Lung, and Blood Institute, NIH, Bethesda, Maryland, USA.
18Department of Immunobiology, University of Arizona, Tucson, Arizona, USA.
19VA HealthCare San Diego, San Diego, California, USA.
20Division of Infectious Diseases, Departments of Pathology and Medicine, School of Medicine, University of California San Diego, La Jolla, California, USA.
21Department of Medical Microbiology and Immunology, University of California Davis, Davis, California, USA.
Address correspondence to: Steven M. Holland, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Disease, Building 10/11N248 MSC 1960, Bethesda, Maryland 20892-1960, USA. Phone: 301.402.7684; Email: smh@nih.gov.
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Frelinger, J.
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1Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases (NIAID), NIH, Bethesda, Maryland, USA.
2Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, Maryland, USA.
3Bioinformatics and Computational Biosciences Branch, Office of Cyber Infrastructure and Computational Biology, NIAID, NIH, Bethesda, Maryland, USA.
4Marsico Lung Institute and Cystic Fibrosis Research Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
5Valley Fever Center for Excellence, University of Arizona College of Medicine–Tucson, Tucson, Arizona, USA.
6Department of Respiratory and Critical Care Medicine, Laboratory of Pulmonary Immunology and Inflammation, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China.
7NIAID Collaborative Bioinformatics Resource, NIAID, NIH, Bethesda, Maryland, USA.
8Advanced Biomedical Computational Science, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Frederick, Maryland, USA.
9Department of Internal Medicine, Division of Infectious Diseases, UC Davis Health, Sacramento, California, USA.
10Department of Immunobiology, University of Arizona, Tucson, Arizona, USA.
11Department of Medicine, University of Arizona College of Medicine–Tucson, Tucson, Arizona, USA.
12Center for Biomedical Informatics and Biostatistics and
13The Center for Applied Genetics and Genomic Medicine, Department of Medicine, University of Arizona, Tucson, Arizona, USA.
14Neutrophil Monitoring Laboratory, Applied/Developmental Research Directorate, Leidos Biomedical Research, Inc, Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA.
15Laboratory for Immunopharmacology of Microbial Products, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo, Japan.
16Immunology Service, Department of Laboratory Medicine, Clinical Center and
17Laboratory of Chronic Airway Infection, Pulmonary Branch, National Heart, Lung, and Blood Institute, NIH, Bethesda, Maryland, USA.
18Department of Immunobiology, University of Arizona, Tucson, Arizona, USA.
19VA HealthCare San Diego, San Diego, California, USA.
20Division of Infectious Diseases, Departments of Pathology and Medicine, School of Medicine, University of California San Diego, La Jolla, California, USA.
21Department of Medical Microbiology and Immunology, University of California Davis, Davis, California, USA.
Address correspondence to: Steven M. Holland, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Disease, Building 10/11N248 MSC 1960, Bethesda, Maryland 20892-1960, USA. Phone: 301.402.7684; Email: smh@nih.gov.
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Fierer, J.
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1Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases (NIAID), NIH, Bethesda, Maryland, USA.
2Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, Maryland, USA.
3Bioinformatics and Computational Biosciences Branch, Office of Cyber Infrastructure and Computational Biology, NIAID, NIH, Bethesda, Maryland, USA.
4Marsico Lung Institute and Cystic Fibrosis Research Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
5Valley Fever Center for Excellence, University of Arizona College of Medicine–Tucson, Tucson, Arizona, USA.
6Department of Respiratory and Critical Care Medicine, Laboratory of Pulmonary Immunology and Inflammation, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China.
7NIAID Collaborative Bioinformatics Resource, NIAID, NIH, Bethesda, Maryland, USA.
8Advanced Biomedical Computational Science, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Frederick, Maryland, USA.
9Department of Internal Medicine, Division of Infectious Diseases, UC Davis Health, Sacramento, California, USA.
10Department of Immunobiology, University of Arizona, Tucson, Arizona, USA.
11Department of Medicine, University of Arizona College of Medicine–Tucson, Tucson, Arizona, USA.
12Center for Biomedical Informatics and Biostatistics and
13The Center for Applied Genetics and Genomic Medicine, Department of Medicine, University of Arizona, Tucson, Arizona, USA.
14Neutrophil Monitoring Laboratory, Applied/Developmental Research Directorate, Leidos Biomedical Research, Inc, Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA.
15Laboratory for Immunopharmacology of Microbial Products, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo, Japan.
16Immunology Service, Department of Laboratory Medicine, Clinical Center and
17Laboratory of Chronic Airway Infection, Pulmonary Branch, National Heart, Lung, and Blood Institute, NIH, Bethesda, Maryland, USA.
18Department of Immunobiology, University of Arizona, Tucson, Arizona, USA.
19VA HealthCare San Diego, San Diego, California, USA.
20Division of Infectious Diseases, Departments of Pathology and Medicine, School of Medicine, University of California San Diego, La Jolla, California, USA.
21Department of Medical Microbiology and Immunology, University of California Davis, Davis, California, USA.
Address correspondence to: Steven M. Holland, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Disease, Building 10/11N248 MSC 1960, Bethesda, Maryland 20892-1960, USA. Phone: 301.402.7684; Email: smh@nih.gov.
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1Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases (NIAID), NIH, Bethesda, Maryland, USA.
2Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, Maryland, USA.
3Bioinformatics and Computational Biosciences Branch, Office of Cyber Infrastructure and Computational Biology, NIAID, NIH, Bethesda, Maryland, USA.
4Marsico Lung Institute and Cystic Fibrosis Research Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
5Valley Fever Center for Excellence, University of Arizona College of Medicine–Tucson, Tucson, Arizona, USA.
6Department of Respiratory and Critical Care Medicine, Laboratory of Pulmonary Immunology and Inflammation, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China.
7NIAID Collaborative Bioinformatics Resource, NIAID, NIH, Bethesda, Maryland, USA.
8Advanced Biomedical Computational Science, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Frederick, Maryland, USA.
9Department of Internal Medicine, Division of Infectious Diseases, UC Davis Health, Sacramento, California, USA.
10Department of Immunobiology, University of Arizona, Tucson, Arizona, USA.
11Department of Medicine, University of Arizona College of Medicine–Tucson, Tucson, Arizona, USA.
12Center for Biomedical Informatics and Biostatistics and
13The Center for Applied Genetics and Genomic Medicine, Department of Medicine, University of Arizona, Tucson, Arizona, USA.
14Neutrophil Monitoring Laboratory, Applied/Developmental Research Directorate, Leidos Biomedical Research, Inc, Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA.
15Laboratory for Immunopharmacology of Microbial Products, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo, Japan.
16Immunology Service, Department of Laboratory Medicine, Clinical Center and
17Laboratory of Chronic Airway Infection, Pulmonary Branch, National Heart, Lung, and Blood Institute, NIH, Bethesda, Maryland, USA.
18Department of Immunobiology, University of Arizona, Tucson, Arizona, USA.
19VA HealthCare San Diego, San Diego, California, USA.
20Division of Infectious Diseases, Departments of Pathology and Medicine, School of Medicine, University of California San Diego, La Jolla, California, USA.
21Department of Medical Microbiology and Immunology, University of California Davis, Davis, California, USA.
Address correspondence to: Steven M. Holland, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Disease, Building 10/11N248 MSC 1960, Bethesda, Maryland 20892-1960, USA. Phone: 301.402.7684; Email: smh@nih.gov.
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1Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases (NIAID), NIH, Bethesda, Maryland, USA.
2Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, Maryland, USA.
3Bioinformatics and Computational Biosciences Branch, Office of Cyber Infrastructure and Computational Biology, NIAID, NIH, Bethesda, Maryland, USA.
4Marsico Lung Institute and Cystic Fibrosis Research Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
5Valley Fever Center for Excellence, University of Arizona College of Medicine–Tucson, Tucson, Arizona, USA.
6Department of Respiratory and Critical Care Medicine, Laboratory of Pulmonary Immunology and Inflammation, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China.
7NIAID Collaborative Bioinformatics Resource, NIAID, NIH, Bethesda, Maryland, USA.
8Advanced Biomedical Computational Science, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Frederick, Maryland, USA.
9Department of Internal Medicine, Division of Infectious Diseases, UC Davis Health, Sacramento, California, USA.
10Department of Immunobiology, University of Arizona, Tucson, Arizona, USA.
11Department of Medicine, University of Arizona College of Medicine–Tucson, Tucson, Arizona, USA.
12Center for Biomedical Informatics and Biostatistics and
13The Center for Applied Genetics and Genomic Medicine, Department of Medicine, University of Arizona, Tucson, Arizona, USA.
14Neutrophil Monitoring Laboratory, Applied/Developmental Research Directorate, Leidos Biomedical Research, Inc, Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA.
15Laboratory for Immunopharmacology of Microbial Products, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo, Japan.
16Immunology Service, Department of Laboratory Medicine, Clinical Center and
17Laboratory of Chronic Airway Infection, Pulmonary Branch, National Heart, Lung, and Blood Institute, NIH, Bethesda, Maryland, USA.
18Department of Immunobiology, University of Arizona, Tucson, Arizona, USA.
19VA HealthCare San Diego, San Diego, California, USA.
20Division of Infectious Diseases, Departments of Pathology and Medicine, School of Medicine, University of California San Diego, La Jolla, California, USA.
21Department of Medical Microbiology and Immunology, University of California Davis, Davis, California, USA.
Address correspondence to: Steven M. Holland, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Disease, Building 10/11N248 MSC 1960, Bethesda, Maryland 20892-1960, USA. Phone: 301.402.7684; Email: smh@nih.gov.
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1Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases (NIAID), NIH, Bethesda, Maryland, USA.
2Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, Maryland, USA.
3Bioinformatics and Computational Biosciences Branch, Office of Cyber Infrastructure and Computational Biology, NIAID, NIH, Bethesda, Maryland, USA.
4Marsico Lung Institute and Cystic Fibrosis Research Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
5Valley Fever Center for Excellence, University of Arizona College of Medicine–Tucson, Tucson, Arizona, USA.
6Department of Respiratory and Critical Care Medicine, Laboratory of Pulmonary Immunology and Inflammation, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China.
7NIAID Collaborative Bioinformatics Resource, NIAID, NIH, Bethesda, Maryland, USA.
8Advanced Biomedical Computational Science, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Frederick, Maryland, USA.
9Department of Internal Medicine, Division of Infectious Diseases, UC Davis Health, Sacramento, California, USA.
10Department of Immunobiology, University of Arizona, Tucson, Arizona, USA.
11Department of Medicine, University of Arizona College of Medicine–Tucson, Tucson, Arizona, USA.
12Center for Biomedical Informatics and Biostatistics and
13The Center for Applied Genetics and Genomic Medicine, Department of Medicine, University of Arizona, Tucson, Arizona, USA.
14Neutrophil Monitoring Laboratory, Applied/Developmental Research Directorate, Leidos Biomedical Research, Inc, Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA.
15Laboratory for Immunopharmacology of Microbial Products, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo, Japan.
16Immunology Service, Department of Laboratory Medicine, Clinical Center and
17Laboratory of Chronic Airway Infection, Pulmonary Branch, National Heart, Lung, and Blood Institute, NIH, Bethesda, Maryland, USA.
18Department of Immunobiology, University of Arizona, Tucson, Arizona, USA.
19VA HealthCare San Diego, San Diego, California, USA.
20Division of Infectious Diseases, Departments of Pathology and Medicine, School of Medicine, University of California San Diego, La Jolla, California, USA.
21Department of Medical Microbiology and Immunology, University of California Davis, Davis, California, USA.
Address correspondence to: Steven M. Holland, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Disease, Building 10/11N248 MSC 1960, Bethesda, Maryland 20892-1960, USA. Phone: 301.402.7684; Email: smh@nih.gov.
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1Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases (NIAID), NIH, Bethesda, Maryland, USA.
2Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, Maryland, USA.
3Bioinformatics and Computational Biosciences Branch, Office of Cyber Infrastructure and Computational Biology, NIAID, NIH, Bethesda, Maryland, USA.
4Marsico Lung Institute and Cystic Fibrosis Research Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
5Valley Fever Center for Excellence, University of Arizona College of Medicine–Tucson, Tucson, Arizona, USA.
6Department of Respiratory and Critical Care Medicine, Laboratory of Pulmonary Immunology and Inflammation, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China.
7NIAID Collaborative Bioinformatics Resource, NIAID, NIH, Bethesda, Maryland, USA.
8Advanced Biomedical Computational Science, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Frederick, Maryland, USA.
9Department of Internal Medicine, Division of Infectious Diseases, UC Davis Health, Sacramento, California, USA.
10Department of Immunobiology, University of Arizona, Tucson, Arizona, USA.
11Department of Medicine, University of Arizona College of Medicine–Tucson, Tucson, Arizona, USA.
12Center for Biomedical Informatics and Biostatistics and
13The Center for Applied Genetics and Genomic Medicine, Department of Medicine, University of Arizona, Tucson, Arizona, USA.
14Neutrophil Monitoring Laboratory, Applied/Developmental Research Directorate, Leidos Biomedical Research, Inc, Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA.
15Laboratory for Immunopharmacology of Microbial Products, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo, Japan.
16Immunology Service, Department of Laboratory Medicine, Clinical Center and
17Laboratory of Chronic Airway Infection, Pulmonary Branch, National Heart, Lung, and Blood Institute, NIH, Bethesda, Maryland, USA.
18Department of Immunobiology, University of Arizona, Tucson, Arizona, USA.
19VA HealthCare San Diego, San Diego, California, USA.
20Division of Infectious Diseases, Departments of Pathology and Medicine, School of Medicine, University of California San Diego, La Jolla, California, USA.
21Department of Medical Microbiology and Immunology, University of California Davis, Davis, California, USA.
Address correspondence to: Steven M. Holland, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Disease, Building 10/11N248 MSC 1960, Bethesda, Maryland 20892-1960, USA. Phone: 301.402.7684; Email: smh@nih.gov.
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1Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases (NIAID), NIH, Bethesda, Maryland, USA.
2Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, Maryland, USA.
3Bioinformatics and Computational Biosciences Branch, Office of Cyber Infrastructure and Computational Biology, NIAID, NIH, Bethesda, Maryland, USA.
4Marsico Lung Institute and Cystic Fibrosis Research Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
5Valley Fever Center for Excellence, University of Arizona College of Medicine–Tucson, Tucson, Arizona, USA.
6Department of Respiratory and Critical Care Medicine, Laboratory of Pulmonary Immunology and Inflammation, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China.
7NIAID Collaborative Bioinformatics Resource, NIAID, NIH, Bethesda, Maryland, USA.
8Advanced Biomedical Computational Science, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Frederick, Maryland, USA.
9Department of Internal Medicine, Division of Infectious Diseases, UC Davis Health, Sacramento, California, USA.
10Department of Immunobiology, University of Arizona, Tucson, Arizona, USA.
11Department of Medicine, University of Arizona College of Medicine–Tucson, Tucson, Arizona, USA.
12Center for Biomedical Informatics and Biostatistics and
13The Center for Applied Genetics and Genomic Medicine, Department of Medicine, University of Arizona, Tucson, Arizona, USA.
14Neutrophil Monitoring Laboratory, Applied/Developmental Research Directorate, Leidos Biomedical Research, Inc, Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA.
15Laboratory for Immunopharmacology of Microbial Products, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo, Japan.
16Immunology Service, Department of Laboratory Medicine, Clinical Center and
17Laboratory of Chronic Airway Infection, Pulmonary Branch, National Heart, Lung, and Blood Institute, NIH, Bethesda, Maryland, USA.
18Department of Immunobiology, University of Arizona, Tucson, Arizona, USA.
19VA HealthCare San Diego, San Diego, California, USA.
20Division of Infectious Diseases, Departments of Pathology and Medicine, School of Medicine, University of California San Diego, La Jolla, California, USA.
21Department of Medical Microbiology and Immunology, University of California Davis, Davis, California, USA.
Address correspondence to: Steven M. Holland, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Disease, Building 10/11N248 MSC 1960, Bethesda, Maryland 20892-1960, USA. Phone: 301.402.7684; Email: smh@nih.gov.
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Published September 27, 2022 - More info
JCI Insight. 2022;7(22):e159491. https://doi.org/10.1172/jci.insight.159491.
© 2022 Hsu et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Received: February 18, 2022; Accepted: September 21, 2022
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Results
Description of cohort. We enrolled 67 patients with DCM, predominantly from Arizona, in an exploratory cohort (Tables 1–3). Patients with histories of other invasive fungal infections, HIV infection, or receiving immunosuppression were excluded. Median lymphocyte count was 1.8 × 103/μL (range, 1.28 × 103/μL to 4.3 × 103/μL), median monocyte count was 0.53 × 103/μL (range, 0.3 × 103/μL to 0.74 × 103/μL). Consistent with previous reports (8, 9), most patients were male (n = 44; 65.7%). Median age at enrollment was 41 years (range, 10 months to 85 years). The cohort included individuals with the following genetically determined ancestries: European (n = 20), admixed American and Latino (n = 20), African or African American (n = 18), East Asian (n = 4), South Asian (n = 3), and 2 people whose ancestry was indeterminate. Because Coccidioides exhibits tissue tropisms, we classified dissemination sites as bone (n = 13), CNS (n = 28), or soft tissue (n = 17). There were 9 patients with dissemination to 2 different tissues (n = 6 bone and soft tissue; n = 1 bone and CNS; n = 2 CNS and soft tissue). Forty patients reported other previous infections, including 15 with noninvasive fungal infections (n = 11 dermatophytoses), 27 with viral infections (n = 7 with shingles), and 3 with bacterial infections, (nontuberculous mycobacteria, Staphylococcus, and Salmonella) (Tables 1 and 2). Twelve patients reported recurrent upper respiratory infections, and 7 reported asthma. There were 27 patients without previous invasive infections (Table 3).
Monogenic mutations. To date, only 12 patients with DCM have been described who carried mutations associated with primary immunodeficiencies, all within the IL-12/IFN-γ and STAT3 axes (8, 10, 11). Initial analysis of our patients considered rare, damaging variants, with a focus on the International Union of Immunological Societies list of genes associated with human inborn errors of immunity (12) by which 2 patients were identified with novel nonsense mutations in STAT3 (c.250C>T p.R84* and c.1267C>T p.R423*). No biallelic or dominant mutations were identified in IL12RB1, IFNGR1, STAT1, STAT4, or GATA2. Although the first identified monogenic mutation leading to DCM was identified in a patient with dominant-negative STAT3 leading to autosomal-dominant hyper-IgE syndrome (AD-HIES; ref. 13), the 2 STAT3-haploinsufficient patients did not exhibit AD-HIES characteristics. Similar to the single, previously reported patient with STAT3 haploinsufficiency (14), these 2 patients had unremarkable clinical histories until DCM; both patients developed fatal CNS dissemination.
Identification of DECTIN-1 pathway mutations. Given the paucity of identified monogenic mutations and the limited geographic presence of Coccidioides, we examined our DCM cohort for more common variants. We filtered our whole-exome sequencing data using a 10% minor-allele frequency cutoff and combined annotation-dependent depletion (CADD) score greater than 20 as a prediction of deleteriousness. Hypothesizing that even common defects in fungal recognition could be important, we specifically queried CLEC7A c.714T>G; p.Y238*. CLEC7A encodes DECTIN-1, the C-type lectin pattern recognition receptor for the fungal cell-wall component β-glucan. DECTIN-1 mediates innate fungal recognition, and p.Y238* is associated with familial mucocutaneous candidiasis (15), increased susceptibility to invasive aspergillosis after hematopoietic stem cell transplantation (HSCT) (16), and chronic lung allograft dysfunction after lung transplantation (17). We found homozygous CLEC7A c.714T>G; p.Y238* in 3 of 67 patients with DCM (4.5%) compared with 680 of 141,265 (0.48%) in the reference Genome Aggregation Database [gnomAD, version 2.1 (18)] (P = 0.0027, Fisher’s exact test) (Supplemental Figure 1; supplemental material available online with this article; https://doi.org/10.1172/jci.insight.159491DS1). Additionally, 10 patients with DCM were heterozygous for p.Y238*. Therefore, 13 of 67 patients with DCM (19.4%) carried p.Y238*, a significantly percentage than that found in gnomAD (n = 16,450 of 141,265 [11.6%]; P = 0.0303, Database [gnomAD, version 2.1 (18)] (P = 0.0027, Fisher’s exact test) (Supplemental Figure 1; supplemental material available online with this article; https://doi.org/10.1172/jci.insight.159491DS1). Additionally, 10 patients with DCM were heterozygous for p.Y238*. Therefore, 13 of 67 patients with DCM (19.4%) carried p.Y238*, a significantly percentage than that found in gnomAD (n = 16,450 of 141,265 [11.6%]; P = 0.0303, Fisher’s exact test) (Figure 1A). p.Y238* results in loss of the terminal 10 amino acids of the C-type lectin domain of DECTIN-1, including the key structural residue, Cys241, which forms a disulfide bridge with Cys147 (19) (Supplemental Figure 2).
Figure 1Fungal recognition variants in patients with DCM. (A) Fold-enrichment of CLEC7A, c.714T>G; p.Y238* variant in patients with DCM compared with the gnomAD. Normalized to frequency of homozygous WT or variant carriers in gnomAD. P = 0.0303, Fisher’s exact test. (B) Parallel signaling pathways after β-glucan recognition by DECTIN-1 leading to activation of NF-κB and NFAT transcription factors and production of TNF-α. The figure was created using BioRender. (C) Confocal microscopy of lung from C. posadasii–infected C57BL/6 mouse showing DECTIN-1 (red) localized near endospores (blue) (left), LAMP-1 (green) localization near endospores (middle), and colocalization of DECTIN-1 and LAMP-1 (tan) around endospores (right). (D) Frequency of patients of European ancestry with DCM with PLCG2, c.802C>T; p.R268W genotype normalized to the non–Finnish European population in gnomAD. P = 0.0077 Fisher’s exact test. (E) Particulate β-glucan–induced TNF production by PBMCs from patients (n = 16) or healthy control (HC) participants (n = 12). DECTIN-1 variants (n = 4) include homozygous p.Y238* (filled) and heterozygous p.Y238* (open). Patients withPLCG2 variants (n = 6) include p.R268W heterozygotes (yellow symbols), p.M28L heterozygotes (green symbol), and p.R268W and p.K775R compound heterozygotes (open yellow symbol). Patients in the “other” category (n = 6) lack identified causal variants. P values were calculated using Brown-Forsythe and Welch ANOVA with Dunnett’s T3 multiple comparisons test. (F) Frequency of Y238* among East Asian patients from DCM validation cohort compared with the 1000G and gnomAD.
Fungal recognition by DECTIN-1 is the first step in a signaling cascade (Figure 1B) that activates SRC kinase, leading to phosphorylation of spleen tyrosine kinase (SYK), assembly of the CARD9-BCL10-MALT1 complex, and NF-κB activation. Concurrently, SYK phosphorylates PLCγ2, increasing intracellular Ca++ concentration, and inducing non–CARD9-dependent NFAT pathways (20–22). Upon engagement, DECTIN-1 is endocytosed (23). Although the 70 to 100 micron size of spherules prohibits engulfment, endospores recognized by DECTIN-1 are phagocytosed, localizing to DECTIN-1/LAMP-1–positive phagolysosomes (Figure 1C). In view of the CLEC7A Y238* mutation abundance in our DCM cohort, we screened for additional damaging variants in this fungal recognition pathway. One patient had heterozygous DECTIN-1 p.I223S, and 15 patients carried predicted damaging PLCG2 (encoding PLCγ2) variants. PLCG2 p.R268W was seen in 9 of the 67 patients, including 3 with CLEC7A p.Y238*. Seven of the 9 individuals with PLCG2 p.R268W were among the 20 Europeans in our cohort, significantly more than seen in the non–Finnish European gnomAD population (n = 7 of 20 [35%] vs. 7917 of 62,273 [12.7%]; P = 0.009, Fisher’s exact test) (Figure 1D).
Decreased TNF-α production in response to β-glucan. To identify relevant biologic effects of these variants, PBMCs from patients and healthy control participants were stimulated with purified, particulate β-glucan, a DECTIN-1 agonist, or LPS, a bacterial component that signals through TLR4. In response to LPS, all patients produced normal levels of TNF-α (Supplemental Figure 3A). However, in response to β-glucan, cells from patients with either heterozygous or biallelic DECTIN-1 pathway variants produced significantly less TNF-α than those of control participants (Figure 1E). DECTIN-1 p.Y238* homozygous (filled symbol in Figure 1E) and heterozygous (open symbols in Figure 1E) patient cells showed similar defects in TNF-α production, suggesting that DECTIN-1 p.Y238* is dominant negative (19, 24). Patient cells tested, including PLCG2 R268W and M28L, were impaired in β-glucan–induced TNF-α production, whereas production of IFN-γ, IL-12p70, and IL-17 did not differ between patients and healthy control participants (Supplemental Figures 3, B–D). Two control samples from the NIH blood bank in Maryland also produced minimal TNF-α, suggesting these individuals might also be at risk if exposed. These data show that cells from patients carrying DECTIN-1 pathway variants produced significantly less TNF-α than those of control participants (P < 0.005; Supplemental Figure 2E) in response to β-glucan while retaining normal IFN-γ, IL-12p70, and IL-17 production and normal responses to LPS.
Variant burdens in validation and reference cohorts. Given the mixed population of our cohort, we used ancestry-matched controls from the 1000 Genomes Project (1000G) and a generalized linear model including ancestry principal components. Variant burden across genes and for recurrent variants within the DECTIN-1 signaling pathway were evaluated. Patients with DCM carried more damaging DECTIN-1 variants (P = 0.0206; OR, 3.45 [95% CI, 1.21–9.84]). Specifically, the Y238* variant was seen in 13 members of our cohort (P = 0.0105; OR, 4.05 [95% CI, 1.39–11.84]). Damaging variants across PLCG2 were also overrepresented (P = 0.015; OR, 3.05 [95% CI, 1.24–7.51]), including R268W (P = 0.0025; OR, 5.46 [95% CI, 1.82–16.37]) and N571S (P = 0.0166; OR 26.22 [95% CI, 1.81–379.37]). Within our cohort of 67 patients, 24 (35.8%) carried at least 1 heterozygous variant in the DECTIN-1/PLCγ2 signaling pathway.
To validate our exploratory analysis, we analyzed an independent DCM cohort (Supplemental Tables 1–3) consisting of patients with meningitis (n = 31; mean age, 54 [range, 24–75] years) or without meningitis (n = 80; mean age, 51 [range, 21–86] years), predominantly from California. Patient ancestry was determined using principal component analysis (PCA) and the 1000G as a reference. Previously identified monogenic susceptibility genes IL12RB1, IFNGR1, IFNGR2, STAT1, STAT4, and STAT3 were screened, and no causative mutations were found.
In the DCM validation cohort, specific variants in both CLEC7A and PLCG2 were again overrepresented: CLEC7A I223S (P = 0.0444; OR, 3.44 [95% CI, 1.03–11.50]) and PLCG2 R268W (P = 0.0276; OR, 2.49 [95% CI, 1.11–5.59]). In the overall validation cohort, CLEC7A Y238* did not reach significance; however, 100% of East Asian patients with DCM carried DECTIN-1 pathway variants. These DECTIN-1 pathway variants included Y238* (n = 12 of 14; 85.7%), I223S (n = 1 of 14), and PLCG2 R268W (n = 1 of 14). In contrast, only 4 of 504 East Asians (0.79%) in 1000G (P < 0.0001) and 2 of 9973 (0.02%) of East Asians in gnomAD (P < 0.0001) carried Y238* (Figure 1F). Among the East Asian individuals with DECTIN-1 Y238*, 1 also carried PLCG2 M28L.
Increased risk of dissemination among African Americans and East Asians has been documented extensively (25). Multivariate analysis of coccidioidomycosis in Kern County, California, comparing patients with mild coccidioidomycosis with those with DCM showed an increased risk among African Americans to develop disseminated disease (OR, 4.6 [95% CI, 1.4–15]) (26). Hospitalization data from Arizona and California during 2005–2011 documented increased incidence of hospitalization for coccidioidomycosis among African Americans (8.1 [in 2005] to 16.1 [in 2011] per 100,000) and Asian/Pacific Islanders (8.71 [in 2005] to 14.72 [in 2011] per 100,000) compared with other ethnicities (3.53 [in 2005] to 7.92 [in 2011] per 100,000) (27). Within our validation cohort, presentation of disease by ancestry is consistent with the epidemiologic data, with 80% of African Americans in the cohort presenting with DCM. In contrast, 75% to 80% of those with European or admixed American ancestry presented with primary pulmonary disease (Supplemental Figure 4). These disparities suggest underlying factors affecting fungal control, such as the ones we have demonstrated among the East-Asians within our cohort.
Nonhematopoietic fungal recognition. Heterozygous DECTIN-1 p.Y238* in either donors or recipients is associated with invasive aspergillosis after HSCT (16), demonstrating both hematopoietic and nonhematopoietic contributions of DECTIN-1 p.Y238* to antifungal defense. DECTIN-1 knockdown also impaired β-glucan–induced cytokine production in a pulmonary epithelial cell line (16). We next considered some downstream effects of DECTIN-1 activation. Several NADPH oxidases in the NOX/DUOX family participate in innate immunity by generation of ROS (superoxide or hydrogen peroxide [H2O2]) after stimulation. Recognizing that DECTIN-1 engagement on neutrophils produces superoxide via NADPH–oxidase complex (28), we examined the pulmonary epithelial NADPH–oxidase complex DUOX1/DUOXA1.
Heterodimeric assembly of DUOX1 and its obligate accessory maturation factor, DUOXA1, in the ER enables its transit to the apical surface of specific epithelial cells (29). DUOX1 releases H2O2 in response to calcium-mobilizing agonists because of its 2 intracellular Ca++-sensing EF-hand domains that activate its NADPH oxidase activity. Duox1–/– mice have increased morbidity and mortality when influenza challenged (30). Whereas bi-allelic mutations in DUOX2 and DUOXA2 cause congenital hypothyroidism, heterozygous DUOX2 variants have been implicated in inflammatory bowel disease (IBD) (31). Similar to DUOX2/DUOXA2 in IBD, variants were found throughout DUOX1 and DUOXA1 in our exploratory cohort (Figure 2A, yellow stars).
Figure 2DECTIN-1 signaling drives H2O2 production by DUOX1 and DUOXA1 in HEK cells. (A) DECTIN-1–activated PLCγ2 releases intracellular Ca++, which activates the EF-hand domains of DUOX1, leading to H2O2 production. DUOX1 and DUOXA1 patient variants are highlighted by yellow stars. (B) DUOX1 variants identified in patients with DCM were transfected into HEK Flp-In cells stably expressing WT DUOXA1. Cells were stimulated with ionomycin, and H2O2 production was measured for 60 minutes. Results are the average of triplicate wells presented as the ratio of H2O2 production by variant or WT; each dot represents the average of triplicate wells from a unique experiment. ****P < 0.0001 by ordinary 1-way ANOVA and Dunnett’s multiple comparisons test. Western blot showing decreased protein abundance of several DUOX1 variants after transfection. (C) DUOXA1 variants, identified in patients with DCM, transfected into HEK Flp-In cells stably expressing DUOX1. Measured as in B. P = 0.016 by ordinary 1-way ANOVA and Dunnett’s multiple comparisons test. (D) Hydrogen peroxide production in HEK cells transfected with WT or patient variant DUOX1, DUOXA1, or DECTIN1, or lacking PLCG2 constructs. Results are the average of triplicate wells presented as the ratio of H2O2 production by variant/WT; each dot represents a unique experiment. ****P < 0.0001 using ordinary 1-way ANOVA and Dunnett’s multiple comparisons test.
In contrast to the recurrent DECTIN-1 and PLCG2 variants, DUOX1/DUOXA1 variants were mostly identified in single patients and were found in 10 of 18 African Americans (55.6%), 3 of 20 non-Hispanic Europeans (15.0%), 1 of 20 admixed Americans/Latinos (5.0%), and 1 of 3 South Asians (33.3%). In the validation cohort, 10 of 48 African Americans (20.8%) carried damaging DUOX1/DUOXA1 variants compared with 1 of 14 Europeans (7.1%), 4 of 34 admixed Americans/Latinos (11.8%), and 2 of 14 East Asians (14.3%). For each individual variant we compared the cohort frequency to the gnomAD, version 2.1, population frequency corresponding to patient ancestry (Supplemental Table 4). In the discovery cohort, 10 of 13 variants had a gnomAD population-specific frequency of less than 2.5 per 1000 with 7 of 13 being less than 1 per 1000. The frequency of these rare alleles was higher in both the discovery and validation cohorts compared with either gnomAD, version 2.1, ancestry-specific population frequency or the gnomAD, version 2.1, frequency for all populations (Supplemental Figure 5).
To evaluate the identified DUOX1/DUOXA1 variants, Flp-In 293 cells stably expressing WT DUOXA1 were transfected with HA-tagged DUOX1; 3 DUOX1 variants exhibited decreased protein stability and did not produce H2O2 after stimulation with ionomycin, despite overexpression (Figure 2B). Similarly, Flp-In 293 cells expressing DUOX1 were transfected with V5-tagged DUOXA1 variants. One identified variant, p.R56Q, previously reported to have compromised H2O2 production (32), showed significantly decreased H2O2 production (Figure 2C).
Given the expression of DECTIN-1 by bronchial epithelial cells (33), we hypothesized that DECTIN-1 activation by fungal components and subsequent PLCγ2-dependent intracellular Ca++ increase might activate DUOX1 through its Ca++-sensing EF-hand domains, causing H2O2 production. HEK-293 cells cotransfected with WT DUOX1, DUOXA1, DECTIN-1, and PLCG2 constructs were stimulated with ionomycin or depleted zymosan, a β-glucan preparation from Saccharomyces cerevisiae that does not activate TLRs, resulting in measurable H2O2 production (Supplemental Figure 6). Substituting WT DUOX1, DUOXA1, or DECTIN-1 with patient variants or replacing PLCG2 with GFP abrogated zymosan-induced H2O2 production (Figure 2D). PLCG2 p.R268W supported H2O2 production in the overexpressed transfection system (data not shown), but primary PBMCs from patients with that variant did not upregulate TNF-α after β-glucan stimulation, suggesting a more complex underlying mechanism for this variant. Although cells transfected with DECTIN-1 Y238* did not produce DUOX1/DUOXA1–derived H2O2, individuals carrying DECTIN-1 Y238* had normal neutrophil superoxide production in both the homozygous and heterozygous states (Supplemental Figure 7).
Next, we wanted to assess whether these variants were specific risk factors for dissemination or infection. Within the validation cohort, there were 59 patients with chronic pulmonary coccidioidomycosis, defined as having treatment refractory (longer than 1 year) disease without extrapulmonary dissemination. Repeating the ancestry matching and 1:4 case to control ratio in DCM plus chronic disease, CLEC7A remained significantly overrepresented (P = 0.0041; OR, 2.058 [95% CI, 1.26–3.37]) with p.I223S (P = 0.0128; OR, 3.712 [95% CI, 1.32–10.426]) and p.Y238* (P = 0.0564; OR, 1.735 [95% CI, 0.985–3.058]) at or near significance. At the gene level, neither PLCG2 nor DUOX1/DUOXA1 were significant (P = 0.596 and 0.805, respectively), while at the variant level, PLCG2 p.R268W no longer reached significance (P = 0.0859).
We next expanded the analysis to include individuals with primary pulmonary disease, defined as those patients who sought treatment and cleared the infection with no further disease more than 1 year after treatment. We had 65 patients with primary pulmonary disease recruited from Arizona as well as 298 patients from the validation cohort. Including these individuals to look at infection risk rather than dissemination, we performed a 1:2 case to control ratio analysis. PLCG2 was significantly overrepresented at the gene level in the discovery cohort (P = 0.0133) with p.R268W and p.N571S reaching variant-level significance (P = 0.025 and 0.0024, respectively). In contrast, no gene reached significance in the validation cohort and only PLCG2 p.N571S reached significance at the variant level (P = 0.036) as underrepresented. Taken together, these data suggest variants in the CLEC7A/PLCG2/DUOX1/DUOXA1 pathway are not risk factors for primary infection but rather for control of infection (CLEC7A) and dissemination (PLCG2/DUOX1/DUOXA1).
In total, STAT3 haploinsufficient mutations, variants in the DECTIN-1 fungal recognition pathway and H2O2-producing pathways involving DUOX1/DUOXA1 were found in 34 of 67 patients with DCM (50.7%) (Figure 3), spanning fungal recognition and response in both hematopoietic and nonhematopoietic compartments.
Figure 3Exploratory cohort: 34 patients with DCM with identified fungal pattern recognition pathway or DUOX1 / DUOXA1 variants.
