AUTHOR=Kim Seok-Joo , Carestia Agostina , McDonald Braedon , Zucoloto Amanda Z. , Grosjean Heidi , Davis Rachelle P. , Turk Madison , Naumenko Victor , Antoniak Silvio , Mackman Nigel , Abdul-Cader Mohamed Sarjoon , Abdul-Careem Mohamed Faizal , Hollenberg Morley D. , Jenne Craig N. TITLE=Platelet-Mediated NET Release Amplifies Coagulopathy and Drives Lung Pathology During Severe Influenza Infection JOURNAL=Frontiers in Immunology VOLUME=12 YEAR=2021 URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2021.772859 DOI=10.3389/fimmu.2021.772859 ISSN=1664-3224 ABSTRACT=

The influenza A virus (IAV) causes a respiratory tract infection with approximately 10% of the population infected by the virus each year. Severe IAV infection is characterized by excessive inflammation and tissue pathology in the lungs. Platelet and neutrophil recruitment to the lung are involved in the pathogenesis of IAV, but the specific mechanisms involved have not been clarified. Using confocal intravital microscopy in a mouse model of IAV infection, we observed profound neutrophil recruitment, platelet aggregation, neutrophil extracellular trap (NET) production and thrombin activation within the lung microvasculature in vivo. Importantly, deficiency or antagonism of the protease-activated receptor 4 (PAR4) reduced platelet aggregation, NET production, and neutrophil recruitment. Critically, inhibition of thrombin or PAR4 protected mice from virus-induced lung tissue damage and edema. Together, these data imply thrombin-stimulated platelets play a critical role in the activation/recruitment of neutrophils, NET release and directly contribute to IAV pathogenesis in the lung.