Platelet-Mediated NET Release Amplifies Coagulopathy and Drives Lung Pathology During Severe Influenza Infection.

Seok-Joo Kim,Mohamed Faizal Abdul-Careem,Morley D Hollenberg,Craig N Jenne,Nigel Mackman,Victor Naumenko,Rachelle P Davis,Heidi Grosjean,Mohamed Sarjoon Abdul-Cader,Braedon Mcdonald,Madison Turk,Agostina Carestia,Silvio Antoniak,Amanda Z Zucoloto

doi:10.3389/fimmu.2021.772859

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.

Highlights

Influenza is a common respiratory tract infection and a leading cause of death from infectious disease in United States [1]
Using high-resolution confocal intravital microscopy (IVM), we demonstrate that collaboration between thrombin, platelets, and neutrophil extracellular trap (NET) leads to enhanced inflammation and tissue damage during influenza A virus (IAV) infection
Using a fluorescent enzyme substrate and a proteaseactivated receptor 4 (PAR4) inhibitor, we demonstrate that thrombin, via platelet activation, is a principal driver of IAVmediated lung pathogenesis

Summary

Introduction

Influenza is a common respiratory tract infection and a leading cause of death from infectious disease in United States [1]. Though important for Platelets Drive Influenza-Induced Inflammation pathogen clearance, innate immunity has the capacity to cause collateral damage and subsequent organ dysfunction if not properly regulated. Neutrophils mediate host-defense against a wide variety of invading microorganisms, possessing a broad arsenal of defense strategies, including release of neutrophil extracellular traps (NETs); highly charged mixtures of decondensed DNA, nuclear, and granular proteins. These structures entrap and kill pathogens and can neutralize viral particles [11]

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Conclusion