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Extrapulmonary Aspergillus infection in patients with CARD9 deficiency
Nikolaus Rieber, … , Taco W. Kuijpers, Michail S. Lionakis
Nikolaus Rieber, … , Taco W. Kuijpers, Michail S. Lionakis
Published October 20, 2016
Citation Information: JCI Insight. 2016;1(17):e89890. https://doi.org/10.1172/jci.insight.89890.
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Research Article Immunology Infectious disease

Extrapulmonary Aspergillus infection in patients with CARD9 deficiency

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Abstract

Invasive pulmonary aspergillosis is a life-threatening mycosis that only affects patients with immunosuppression, chemotherapy-induced neutropenia, transplantation, or congenital immunodeficiency. We studied the clinical, genetic, histological, and immunological features of 2 unrelated patients without known immunodeficiency who developed extrapulmonary invasive aspergillosis at the ages of 8 and 18. One patient died at age 12 with progressive intra-abdominal aspergillosis. The other patient had presented with intra-abdominal candidiasis at age 9, and developed central nervous system aspergillosis at age 18 and intra-abdominal aspergillosis at age 25. Neither patient developed Aspergillus infection of the lungs. One patient had homozygous M1I CARD9 (caspase recruitment domain family member 9) mutation, while the other had homozygous Q295X CARD9 mutation; both patients lacked CARD9 protein expression. The patients had normal monocyte and Th17 cell numbers in peripheral blood, but their mononuclear cells exhibited impaired production of proinflammatory cytokines upon fungus-specific stimulation. Neutrophil phagocytosis, killing, and oxidative burst against Aspergillus fumigatus were intact, but neither patient accumulated neutrophils in infected tissue despite normal neutrophil numbers in peripheral blood. The neutrophil tissue accumulation defect was not caused by defective neutrophil-intrinsic chemotaxis, indicating that production of neutrophil chemoattractants in extrapulmonary tissue is impaired in CARD9 deficiency. Taken together, our results show that CARD9 deficiency is the first known inherited or acquired condition that predisposes to extrapulmonary Aspergillus infection with sparing of the lungs, associated with impaired neutrophil recruitment to the site of infection.

Authors

Nikolaus Rieber, Roel P. Gazendam, Alexandra F. Freeman, Amy P. Hsu, Amanda L. Collar, Janyce A. Sugui, Rebecca A. Drummond, Chokechai Rongkavilit, Kevin Hoffman, Carolyn Henderson, Lily Clark, Markus Mezger, Muthulekha Swamydas, Maik Engeholm, Rebecca Schüle, Bettina Neumayer, Frank Ebel, Constantinos M. Mikelis, Stefania Pittaluga, Vinod K. Prasad, Anurag Singh, Joshua D. Milner, Kelli W. Williams, Jean K. Lim, Kyung J. Kwon-Chung, Steven M. Holland, Dominik Hartl, Taco W. Kuijpers, Michail S. Lionakis

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Figure 3

Caspase recruitment domain family member 9 (CARD9) deficiency results in impaired production of proinflammatory mediators upon fungal-specific stimulation.

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Caspase recruitment domain family member 9 (CARD9) deficiency results in...
IL-1β (A; *P = 0.0275, Mann-Whitney test) and IL-6 (B; *P = 0.0275, Mann-Whitney test) production by healthy donor (n = 6–12) and patient 1 (n = 2–4 independent experiments) peripheral blood mononuclear cells (PBMCs) after 24 hours of stimulation with live Candida albicans or Staphylococcus aureus or after 24 hours without stimulation. IL-1β (C; ***P = 0.0002, unpaired t test), IL-6 (D; **P = 0.0019, unpaired t test), TNF-α (E; ****P < 0.0001, unpaired t test) and GM-CSF (F; ***P = 0.0008, unpaired t test) production by healthy donor (n = 7–10) and patient 2 (n = 3 independent experiments) PBMCs after 48 hours of stimulation with heat-killed C. albicans or LPS or after 48 hours without stimulation. Data represent the mean ± SEM.

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