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Infectious diseases

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Immunogenetics associated with severe coccidioidomycosis
Amy P. Hsu, … , Michail S. Lionakis, Steven M. Holland
Amy P. Hsu, … , Michail S. Lionakis, Steven M. Holland
Published September 27, 2022
Citation Information: JCI Insight. 2022. https://doi.org/10.1172/jci.insight.159491.
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Immunogenetics associated with severe coccidioidomycosis

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Abstract

Disseminated coccidioidomycosis (DCM) is caused by Coccidioides, pathogenic fungi endemic to the Southwestern United States and Mexico. Illness occurs in approximately 30% of those infected, <1% of whom develop disseminated disease. To address why some individuals allow dissemination, we enrolled DCM patients and performed whole-exome sequencing. In an exploratory set of 67 DCM patients, two had haploinsufficient STAT3 mutations, while defects in β-glucan sensing and response were seen in 34/67 (50.7%) cases. Damaging CLEC7A (n=14) and PLCG2 (n=11) variants were associated with impaired production of β-glucan-stimulated TNF-α from peripheral blood mononuclear cells compared to healthy controls (P<0.005). Using ancestry-matched controls, damaging CLEC7A and PLCG2 variants were over-represented in DCM (P=0.0206, P=0.015, respectively) including CLEC7A Y238* (P=0.0105) and PLCG2 R268W (P=0.0025). A validation cohort of 111 DCM patients confirmed PLCG2 R268W (P=0.0276), CLEC7A I223S (P=0.044), and CLEC7A Y238* (P=0.0656). Stimulation with a DECTIN-1 agonist induced DUOX1/DUOXA1-derived H2O2 in transfected cells. Heterozygous DUOX1 or DUOXA1 variants which impaired H2O2 production were overrepresented in discovery and validation cohorts. Patients with DCM have impaired β-glucan sensing or response affecting TNF-α and H2O2 production. Impaired Coccidioides recognition and decreased cellular response are associated with disseminated coccidioidomycosis.

Authors

Amy P. Hsu, Agnieszka Korzeniowska, Cynthia C. Aguilar, Jingwen Gu, Eric Karlins, Andrew J. Oler, Gang Chen, Glennys V. Reynoso, Joie Davis, Alexandria Chaput, Tao Peng, Ling Sun, Justin B. Lack, Derek J. Bays, Ethan R. Stewart, Sarah E. Waldman, Daniel A. Powell, Fariba M. Donovan, Jigar V. Desai, Nima Pouladi, Debra A. Long Priel, Daisuke Yamanaka, Sergio D. Rosenzweig, Julie E. Niemela, Jennifer Stoddard, Alexandra F. Freeman, Christa S. Zerbe, Douglas B. Kuhns, Yves A. Lussier, Kenneth N. Olivier, Richard C. Boucher, Heather D. Hickman, Jeffrey Frelinger, Joshua Fierer, Lisa F. Shubitz, Thomas L. Leto, George R. Thompson III, John N. Galgiani, Michail S. Lionakis, Steven M. Holland

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Hyperglycemia exacerbates dengue virus infection by facilitating poly(A)-binding protein-mediated viral translation
Ting-Jing Shen, … , Chia-Yi Yu, Chiou-Feng Lin
Ting-Jing Shen, … , Chia-Yi Yu, Chiou-Feng Lin
Published September 20, 2022
Citation Information: JCI Insight. 2022. https://doi.org/10.1172/jci.insight.142805.
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Hyperglycemia exacerbates dengue virus infection by facilitating poly(A)-binding protein-mediated viral translation

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Abstract

Diabetes mellitus (DM) is highly comorbid with severe dengue diseases; however, the underlying mechanisms are unclear. DM patients display a 1.61-fold increased risk of developing dengue hemorrhagic fever. In search of host factors involved in DENV infection, this study utilizes high glucose (HG) treatment and shows that HG increases viral protein expression and virion release but has no effects on the early stages of viral infection. Following HG stimulation, DEN-Luc-transfected assay and cellular replicon-based assay display increased viral translation, while using the glucose uptake inhibitor phloretin blocks this effect. HG treatment increases the translational factor poly(A)-binding protein (PABP) in a glucose transporter-associated PI3K/AKT-regulated manner. Silencing PABP significantly decreases HG-prompted virion production. HG enhances the formation of the PABP-eIF4G complex, which is regulated by protein-disulfide isomerase. Hyperglycemia increases PABP expression, mortality, viral protein expression, and viral loads in streptozotocin-induced DM mice. Overall, hyperglycemic stress facilitates DENV infection by strengthening PABP-mediated viral translation.

Authors

Ting-Jing Shen, Chia-Ling Chen, Tsung-Ting Tsai, Ming-Kai Jhan, Chyi-Huey Bai, Yu-Chun Yen, Ching-Wen Tsai, Cheng-Yi Lee, Po-Chun Tseng, Chia-Yi Yu, Chiou-Feng Lin

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CLEC5A is critical in Pseudomonas aeruginosa-induced acute lung injury
Pei-Shan Sung, … , Cheng-Hsun Chiu, Shie-Liang Hsieh
Pei-Shan Sung, … , Cheng-Hsun Chiu, Shie-Liang Hsieh
Published September 1, 2022
Citation Information: JCI Insight. 2022. https://doi.org/10.1172/jci.insight.156613.
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CLEC5A is critical in Pseudomonas aeruginosa-induced acute lung injury

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Abstract

Pseudomonas aeruginosa is one of the most common nosocomial infections worldwide, and frequently causes ventilator-associated acute pneumonia in immunocompromised patients. Abundant neutrophil extracellular traps (NETs) contribute to acute lung injury, thereby aggravating ventilator-induced lung damage. While pattern recognition receptors (PRRs) TLR4 and TLR5 are required for host defense against P. aeruginosa invasion, the PRR responsible for P. aeruginosa-induced NET formation, proinflammatory cytokine release, and acute lung injury remains unclear. We found that myeloid C-type lectin domain family 5 member A (CLEC5A) interacts with lipopolysaccharides of P. aeruginosa, and is responsible for P. aeruginosa-induced NET formation and lung inflammation. P. aeruginosa activates CLEC5A to induce caspase-1-dependent NET formation, but it neither causes gasdermin D (GSDMD) cleavage nor contributes to P. aeruginosa-induced neutrophil death. Blockade of CLEC5A attenuates P. aeruginosa-induced NETosis and lung injury, and simultaneous administration of anti-CLEC5A mAb with ciprofloxacin increases survival rate and decreases collagen deposition in the lungs of mice challenged with a lethal dose of P. aeruginosa. Thus, CLEC5A is a promising therapeutic target to reduce ventilator-associated lung injury and fibrosis in P. aeruginosa-induced pneumonia.

Authors

Pei-Shan Sung, Yu-Chun Peng, Shao-Ping Yang, Cheng-Hsun Chiu, Shie-Liang Hsieh

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SARS-CoV-2 reinfections during the Delta and Omicron waves
C. Paul Morris, … , Eili Y. Klein, Heba H. Mostafa
C. Paul Morris, … , Eili Y. Klein, Heba H. Mostafa
Published September 1, 2022
Citation Information: JCI Insight. 2022. https://doi.org/10.1172/jci.insight.162007.
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SARS-CoV-2 reinfections during the Delta and Omicron waves

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Abstract

BACKGROUND. Increased reinfection rates with SARS-CoV-2 have recently been reported, with some locations basing reinfection on a second positive PCR test at least 90 days after initial infection. In this study, we used the Johns Hopkins SARS-CoV-2 genomic surveillance data to evaluate the frequency of sequencing validated, confirmed and inferred reinfections between March 2020 and July 2022. METHODS. Patients who had two or more positive SARS-CoV-2 tests in our system with samples sequenced as a part of our surveillance efforts were identified as the cohort for our study. SARS-CoV-2 genomes of patients’ initial and later samples were compared. RESULTS. A total of 755 patients (920 samples) had a positive test at least 90 days after the initial test with a median time between tests of 377 days. Sequencing was attempted on 231 samples and was successful in 127. Successful sequencing spiked during the Omicron surge and showed higher median days from initial infection compared to failed sequences. A total of 122 (98%) patients showed evidence of reinfection, 45 of which had sequence validated reinfection and 77 had inferred reinfections (later sequence showed a clade that was not circulating when the patient was initially infected). Of 45 sequence validated reinfections, 43 (96%) were caused by the Omicron variant, 41 (91%) were symptomatic, 32 (71%) were vaccinated prior to the second infection, 6 (13%) were Immunosuppressed, and only 2 (4%) were hospitalized. CONCLUSIONS. Sequence validated reinfections increased with the Omicron variant but were generally associated with mild infections.

Authors

C. Paul Morris, Raghda E. Eldesouki, Amary Fall, David C. Gaston, Julie M. Norton, Nicholas D. Gallagher, Chun Huai Luo, Omar Abdullah, Eili Y. Klein, Heba H. Mostafa

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Germline IgM predicts T-cell immunity to Pneumocystis
Kristin Noell, … , Samuel J. Landry, Jay K. Kolls
Kristin Noell, … , Samuel J. Landry, Jay K. Kolls
Published August 2, 2022
Citation Information: JCI Insight. 2022. https://doi.org/10.1172/jci.insight.161450.
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Germline IgM predicts T-cell immunity to Pneumocystis

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Abstract

Pneumocystis is the most common fungal pulmonary infection in children under 5. In children with primary immunodeficiency, Pneumocystis often presents at 3-6 months that coincides with the nadir of maternal IgG and where IgM is the dominant immunoglobulin isotype. Since B cells are the dominant antigen-presenting cells for Pneumocystis, we hypothesized the presence of fungal specific IgMs in human and mice and that these IgM specificities would predict T cell antigens. We detected fungal specific IgMs in human and mouse serum and utilized immunoprecipitation to determine if any antigens were similar across donors. We then assessed T cell responses to these antigens. We found anti-Pneumocystis IgM in wild-type mice as well as Aicda-/- mice and in human cord blood. Immunoprecipitation of Pneumocystis murina with human cord blood identified shared antigens among these donors. Using class II MHC binding prediction, we designed peptides with these antigens and identified robust peptide specific lung T cell responses after P. murina infection. After mice were immunized with two of the antigens, adoptive transfer of vaccine elicited CD4+ T cells showed effector activity suggesting that these antigens contain protective Pneumocystis epitopes. These data support the notion that germline encoded IgM B-cell receptors are critical in antigen presentation and T cell priming in early Pneumocystis infection.

Authors

Kristin Noell, Guixiang Dai, Dora Pungan, Anna Ebacher, Janet E. McCombs, Samuel J. Landry, Jay K. Kolls

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Ebola virus protein VP40 stimulates IL-12- and IL-18-dependent activation of human natural killer cells
Hung Le, … , Stephen N. Waggoner, Karnail Singh
Hung Le, … , Stephen N. Waggoner, Karnail Singh
Published July 21, 2022
Citation Information: JCI Insight. 2022. https://doi.org/10.1172/jci.insight.158902.
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Ebola virus protein VP40 stimulates IL-12- and IL-18-dependent activation of human natural killer cells

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Abstract

Accumulation of activated natural killer (NK) cells in tissues during Ebola virus infection contributes to Ebola virus disease (EVD) pathogenesis. Yet, immunization with Ebola virus-like particles (VLPs) comprising glycoprotein (GP) and matrix protein VP40 provides rapid, NK cell-mediated protection against Ebola challenge. We used Ebola VLPs as the viral surrogates to elucidate the molecular mechanism by which Ebola virus triggers heightened NK cell activity. Incubation of human peripheral blood mononuclear cells (PBMCs) with Ebola VLPs or VP40 protein led to increased expression of IFN-γ, TNF-α, granzyme B, and perforin by CD3-CD56+ NK cells, along with concomitant increase in degranulation and cytotoxic activity of these cells. Optimal activation required accessory cells like CD14+ myeloid and CD14- cells and triggered increased secretion of numerous inflammatory cytokines. VP40-induced IFN-γ and TNF-α secretion by NK cells was dependent on IL-12 and IL-18 and suppressed by IL-10. In contrast, their increased degranulation was dependent on IL-12 with little influence of IL-18 or IL-10. These results demonstrate that Ebola VP40 stimulates NK cell functions in an IL-12 and IL-18 dependent manner that involves CD14+ and CD14- accessory cells. These novel findings may help in designing improved intervention strategies required to control viral transmission during Ebola outbreaks.

Authors

Hung Le, Paul Spearman, Stephen N. Waggoner, Karnail Singh

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Multicenter analysis of neutrophil extracellular trap dysregulation in adult and pediatric COVID-19
Carmelo Carmona-Rivera, … , Luigi D. Notarangelo, Mariana J. Kaplan
Carmelo Carmona-Rivera, … , Luigi D. Notarangelo, Mariana J. Kaplan
Published July 19, 2022
Citation Information: JCI Insight. 2022. https://doi.org/10.1172/jci.insight.160332.
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Multicenter analysis of neutrophil extracellular trap dysregulation in adult and pediatric COVID-19

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Abstract

Dysregulation in neutrophil extracellular trap (NET) formation and degradation may play a role in the pathogenesis and severity of COVID-19; however, its role in the pediatric manifestations of this disease including multisystem inflammatory syndrome in children (MIS-C) and chilblain-like lesions (CLL), otherwise known as “COVID toes”, remains unclear. Studying multinational cohorts, we found that, in CLL, NETs were significantly increased in serum and skin. There was geographic variability in the prevalence of increased NETs in MIS-C, in association with disease severity. MIS-C and CLL serum samples displayed decreased NET degradation ability, in association with C1q and G-actin or anti-NET antibodies, respectively, but not with genetic variants of DNases. In adult COVID-19, persistent elevations in NETs post-disease diagnosis were detected but did not occur in asymptomatic infection. COVID-19-affected adults displayed significant prevalence of impaired NET degradation, in association with anti-DNase1L3, G-actin, and specific disease manifestations, but not with genetic variants of DNases. NETs were detected in many organs of adult patients who died from COVID-19 complications. Infection with the Omicron variant was associated with decreased levels of NETs when compared to other SARS-CoV-2 strains. These data support a role for NETs in the pathogenesis and severity of COVID-19 in pediatric and adult patients.

Authors

Carmelo Carmona-Rivera, Yu Zhang, Kerry Dobbs, Tovah E. Markowitz, Clifton L. Dalgard, Andrew J. Oler, Dillon R. Claybaugh, Deborah Draper, Meng Truong, Ottavia M. Delmonte, Francesco Licciardi, Ugo Ramenghi, Nicoletta Crescenzio, Luisa Imberti, Alessandra Sottini, Virginia Quaresima, Chiara Fiorini, Valentina Discepolo, Andrea Lo Vecchio, Alfredo Guarino, Luca Pierri, Andrea Catzola, Andrea Biondi, Paolo Bonfanti, Maria Cecilia Poli Harlowe, Yazmin Espinosa, Camila A. Astudillo, Emma Rey-Jurado, Cecilia Vial, Javiera De la Cruz, Ricardo Gonzalez, Cecilia Pinera, Jacqueline W. Mays, Ashley Ng, Andrew Platt, Beth A. Drolet, John Moon, Edward W. Cowen, Heather Kenney, Sarah E. Weber, Riccardo Castagnoli, Mary K. Magliocco, Michael Austin Stack, Gina A. Montealegre Sanchez, Karyl Barron, Danielle L. Fink, Douglas B. Kuhns, Stephen M. Hewitt, Lisa M. Arkin, Daniel S. Chertow, Helen C. Su, Luigi D. Notarangelo, Mariana J. Kaplan

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Junctional adhesion molecule-A deletion increases phagocytosis and improves survival in a murine model of sepsis
Nathan J. Klingensmith, … , Mandy L. Ford, Craig M. Coopersmith
Nathan J. Klingensmith, … , Mandy L. Ford, Craig M. Coopersmith
Published July 12, 2022
Citation Information: JCI Insight. 2022. https://doi.org/10.1172/jci.insight.156255.
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Junctional adhesion molecule-A deletion increases phagocytosis and improves survival in a murine model of sepsis

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Abstract

The tight junction-associated protein Junctional Adhesion Molecule-A (JAM-A) is increased in sepsis although the significance of this is unknown. Here we show that septic JAM-A-/- mice have increased gut permeability. Paradoxically, septic JAM-A-/- mice have decreased bacteremia and systemic TNF and IL-1β. Survival is improved in JAM-A-/- mice. However intestine-specific JAM-A-/- deletion does not alter mortality suggesting the mortality benefit conferred in mice lacking JAM-A is independent of the intestine. Septic JAM-A-/- mice have increased splenic CD44hiCD4+ T cells with decreased frequency of TNF+CD4+ cells and elevated frequency of IL-2+CD4+ cells. Septic JAM-A-/- mice have increased B cells in mesenteric lymph nodes with elevated serum IgA and intraepithelial lymphocyte IgA production. JAM-A-/- x RAG -/- mice have improved survival compared to RAG-/- mice and identical mortality as WT mice. Gut neutrophil infiltration is increased in JAM-A-/- mice and neutrophil phagocytosis is increased. Septic JAM-A-/- mice depleted of neutrophils lose their survival advantage. Therefore increased bacterial clearance via neutrophils and an altered systemic inflammatory response with increased opsonizing IgA produced through the adaptive immune system results in improved survival in septic JAM-A-/- mice. JAM-A may be a therapeutic target in sepsis via immune mechanisms not related to its role in permeability.

Authors

Nathan J. Klingensmith, Katherine T Fay, David A. Swift, Julia M.R. Bazzano, John D. Lyons, Ching-wen Chen, Mei Meng, Kimberly M. Ramonell, Zhe Liang, Eileen M. Burd, Charles A. Parkos, Mandy L. Ford, Craig M. Coopersmith

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Anti-nucleocapsid antibody levels and pulmonary comorbid conditions are linked to post–COVID-19 syndrome
Xiaolin Jia, … , Sharon Chinthrajah, Kari C. Nadeau
Xiaolin Jia, … , Sharon Chinthrajah, Kari C. Nadeau
Published July 8, 2022
Citation Information: JCI Insight. 2022;7(13):e156713. https://doi.org/10.1172/jci.insight.156713.
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Anti-nucleocapsid antibody levels and pulmonary comorbid conditions are linked to post–COVID-19 syndrome

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Abstract

BACKGROUND Prolonged symptoms after SARS-CoV-2 infection are well documented. However, which factors influence development of long-term symptoms, how symptoms vary across ethnic groups, and whether long-term symptoms correlate with biomarkers are points that remain elusive.METHODS Adult SARS-CoV-2 reverse transcription PCR–positive (RT-PCR–positive) patients were recruited at Stanford from March 2020 to February 2021. Study participants were seen for in-person visits at diagnosis and every 1–3 months for up to 1 year after diagnosis; they completed symptom surveys and underwent blood draws and nasal swab collections at each visit.RESULTS Our cohort (n = 617) ranged from asymptomatic to critical COVID-19 infections. In total, 40% of participants reported at least 1 symptom associated with COVID-19 six months after diagnosis. Median time from diagnosis to first resolution of all symptoms was 44 days; median time from diagnosis to sustained symptom resolution with no recurring symptoms for 1 month or longer was 214 days. Anti-nucleocapsid IgG level in the first week after positive RT-PCR test and history of lung disease were associated with time to sustained symptom resolution. COVID-19 disease severity, ethnicity, age, sex, and remdesivir use did not affect time to sustained symptom resolution.CONCLUSION We found that all disease severities had a similar risk of developing post–COVID-19 syndrome in an ethnically diverse population. Comorbid lung disease and lower levels of initial IgG response to SARS-CoV-2 nucleocapsid antigen were associated with longer symptom duration.TRIAL REGISTRATION ClinicalTrials.gov, NCT04373148.FUNDING NIH UL1TR003142 CTSA grant, NIH U54CA260517 grant, NIEHS R21 ES03304901, Sean N Parker Center for Allergy and Asthma Research at Stanford University, Chan Zuckerberg Biohub, Chan Zuckerberg Initiative, Sunshine Foundation, Crown Foundation, and Parker Foundation.

Authors

Xiaolin Jia, Shu Cao, Alexandra S. Lee, Monali Manohar, Sayantani B. Sindher, Neera Ahuja, Maja Artandi, Catherine A. Blish, Andra L. Blomkalns, Iris Chang, William J. Collins, Manisha Desai, Hena Naz Din, Evan Do, Andrea Fernandes, Linda N. Geng, Yael Rosenberg-Hasson, Megan Ruth Mahoney, Abigail L. Glascock, Lienna Y. Chan, Sharon Y. Fong, CLIAHUB Consortium, Chan Zuckerberg Biohub, Maira Phelps, Olivia Raeber, Stanford COVID-19 Biobank Study Group, Natasha Purington, Katharina Röltgen, Angela J. Rogers, Theo Snow, Taia T. Wang, Daniel Solis, Laura Vaughan, Michelle Verghese, Holden Maecker, Richard Wittman, Rajan Puri, Amy Kistler, Samuel Yang, Scott D. Boyd, Benjamin A. Pinsky, Sharon Chinthrajah, Kari C. Nadeau

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Nanoparticles reduce monocytes within the lungs to improve outcomes after influenza virus infection in aged mice
William J. Kelley, … , Adam Elhofy, Daniel R. Goldstein
William J. Kelley, … , Adam Elhofy, Daniel R. Goldstein
Published June 23, 2022
Citation Information: JCI Insight. 2022. https://doi.org/10.1172/jci.insight.156320.
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Nanoparticles reduce monocytes within the lungs to improve outcomes after influenza virus infection in aged mice

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Abstract

Older people exhibit dysregulated innate immunity to respiratory viral infections, including influenza and SARS-CoV-2, to increase morbidity and mortality. Nanoparticles are a potential practical therapeutic that could reduce exaggerated innate immune responses within the lungs during viral infection. However, such therapeutics have not been examined for effectiveness during respiratory viral infection, particular in aged hosts. Here, we employed a lethal model of influenza viral infection in vulnerable aged mice to examine the ability of biodegradable, cargo-free nanoparticles, designated ONP-302, to resolve innate immune dysfunction and improve outcomes during infection. We administered ONP-302 via intravenous injection to aged mice at day 3 post-infection when the hyperinflammatory innate immune response is already established. During infection, we found that ONP-302 treatment reduced the numbers of inflammatory monocytes within the lungs and increased their number in both the liver and spleen, without impacting viral clearance. Importantly, cargo-free nanoparticles reduced lung damage, histological lung inflammation and improved gas exchange and, ultimately, the clinical outcomes in influenza-infected aged mice. In conclusion, ONP-302 improves outcomes in influenza-infected aged mice. Thus, our study provides fundamental information concerning a practical therapeutic which, if translated clinically, could improve disease outcomes for vulnerable older patients suffering from respiratory viral infections.

Authors

William J. Kelley, Kathleen M. Wragg, Judy Chen, Tushar Murthy, Qichen Xu, Michael T. Boyne II, Joseph R. Podojil, Adam Elhofy, Daniel R. Goldstein

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