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Inflammation ; 45(4): 1430-1449, 2022 Aug.
Article in English | MEDLINE | ID: covidwho-1756833


Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has resulted in a global pandemic with severe socioeconomic effects. Immunopathogenesis of COVID-19 leads to acute respiratory distress syndrome (ARDS) and organ failure. Binding of SARS-CoV-2 spike protein to human angiotensin-converting enzyme 2 (hACE2) on bronchiolar and alveolar epithelial cells triggers host inflammatory pathways that lead to pathophysiological changes. Proinflammatory cytokines and type I interferon (IFN) signaling in alveolar epithelial cells counter barrier disruption, modulate host innate immune response to induce chemotaxis, and initiate the resolution of inflammation. Here, we discuss experimental models to study SARS-CoV-2 infection, molecular pathways involved in SARS-CoV-2-induced inflammation, and viral hijacking of anti-inflammatory pathways, such as delayed type-I IFN response. Mechanisms of alveolar adaptation to hypoxia, adenosinergic signaling, and regulatory microRNAs are discussed as potential therapeutic targets for COVID-19.

COVID-19 , Humans , Immunity, Innate , Inflammation , SARS-CoV-2 , Spike Glycoprotein, Coronavirus
Eur Respir J ; 59(4)2022 Apr.
Article in English | MEDLINE | ID: covidwho-1526590
Am J Respir Crit Care Med ; 203(9): 1070-1087, 2021 05 01.
Article in English | MEDLINE | ID: covidwho-1223640


Background: This document provides evidence-based clinical practice guidelines on the diagnostic utility of nucleic acid-based testing of respiratory samples for viral pathogens other than influenza in adults with suspected community-acquired pneumonia (CAP).Methods: A multidisciplinary panel developed a Population-Intervention-Comparison-Outcome question, conducted a pragmatic systematic review, and applied Grading of Recommendations, Assessment, Development, and Evaluation methodology for clinical recommendations.Results: The panel evaluated the literature to develop recommendations regarding whether routine diagnostics should include nucleic acid-based testing of respiratory samples for viral pathogens other than influenza in suspected CAP. The evidence addressing this topic was generally adjudicated to be of very low quality because of risk of bias and imprecision. Furthermore, there was little direct evidence supporting a role for routine nucleic acid-based testing of respiratory samples in improving critical outcomes such as overall survival or antibiotic use patterns. However, on the basis of direct and indirect evidence, recommendations were made for both outpatient and hospitalized patients with suspected CAP. Testing for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection was not addressed in the literature at the time of the evidence review.Conclusions: The panel formulated and provided their rationale for recommendations on nucleic acid-based diagnostics for viral pathogens other than influenza for patients with suspected CAP.

Community-Acquired Infections/virology , DNA, Viral/analysis , Pneumonia/virology , Societies, Medical , Viruses/genetics , Community-Acquired Infections/diagnosis , Humans , Pneumonia/diagnosis
Am J Respir Cell Mol Biol ; 63(6): 758-766, 2020 12.
Article in English | MEDLINE | ID: covidwho-733099


Viral pneumonias remain global health threats, as exemplified in the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic, requiring novel treatment strategies both early and late in the disease process. We have reported that mice treated before or soon after infection with a combination of inhaled Toll-like receptor (TLR) 2/6 and 9 agonists (Pam2-ODN) are broadly protected against microbial pathogens including respiratory viruses, but the mechanisms remain incompletely understood. The objective of this study was to validate strategies for immune modulation in a preclinical model of viral pneumonia and determine their mechanisms. Mice were challenged with the Sendai paramyxovirus in the presence or absence of Pam2-ODN treatment. Virus burden and host immune responses were assessed to elucidate Pam2-ODN mechanisms of action and to identify additional opportunities for therapeutic intervention. Enhanced survival of Sendai virus pneumonia with Pam2-ODN treatment was associated with reductions in lung virus burden and with virus inactivation before internalization. We noted that mortality in sham-treated mice corresponded with CD8+ T-cell lung inflammation on days 11-12 after virus challenge, after the viral burden had declined. Pam2-ODN blocked this injurious inflammation by minimizing virus burden. As an alternative intervention, depleting CD8+ T cells 8 days after viral challenge also decreased mortality. Stimulation of local innate immunity within the lungs by TLR agonists early in disease or suppression of adaptive immunity by systemic CD8+ T-cell depletion late in disease improves outcomes of viral pneumonia in mice. These data reveal opportunities for targeted immunomodulation to protect susceptible human subjects.

Immunity, Innate/immunology , Lipopeptides/pharmacology , Pneumonia, Viral/drug therapy , Pneumonia/prevention & control , Respirovirus Infections/drug therapy , Sendai virus/drug effects , Viral Load/drug effects , Animals , Epithelial Cells/drug effects , Epithelial Cells/immunology , Epithelial Cells/virology , Female , Immunity, Innate/drug effects , Lung/drug effects , Lung/immunology , Lung/virology , Mice , Mice, Inbred C57BL , Pneumonia/immunology , Pneumonia/pathology , Pneumonia, Viral/immunology , Pneumonia, Viral/virology , Respirovirus Infections/immunology , Respirovirus Infections/virology , Sendai virus/immunology