AUTHOR=Ferreira André C. , Sacramento Carolina Q. , Pereira-Dutra Filipe S. , Fintelman-Rodrigues Natália , Silva Priscila P. , Mattos Mayara , de Freitas Caroline S. , Marttorelli Andressa , de Melo Gabrielle R. , Campos Mariana M. , Azevedo-Quintanilha Isaclaudia G. , Carlos Aluana S. , Emídio João Vítor , Garcia Cristiana C. , Bozza Patrícia T. , Bozza Fernando A. , Souza Thiago M. L. 

TITLE=Severe influenza infection is associated with inflammatory programmed cell death in infected macrophages

JOURNAL=Frontiers in Cellular and Infection Microbiology

VOLUME=Volume 13 - 2023

YEAR=2023

URL=https://www.frontiersin.org/journals/cellular-and-infection-microbiology/articles/10.3389/fcimb.2023.1067285

DOI=10.3389/fcimb.2023.1067285

ISSN=2235-2988

ABSTRACT=Influenza A virus (IAV) is one of the leading causes of respiratory tract infections in humans, representing a major public health concern. The various types of cell death have a crucial role in IAV pathogenesis because this virus may trigger both apoptosis and necroptosis in airway epithelial cells in parallel. Macrophages play an important role in the clearance of virus particles, priming the adaptive immune response in influenza. However, the contribution of macrophage death to the inflammatory response and pathogenesis of IAV infection remains unclear. In this work, we investigated IAV-induced macrophage death, along with potential therapeutic intervention. We found that IAV or its surface glycoprotein hemagglutinin (HA) triggers inflammatory programmed cell death in human and murine macrophages in a Toll-like receptor-4 (TLR4)- and TNF-dependent manner. Anti-TNF treatment in vivo with the clinically approved drug etanercept prevented the engagement of the lytic programmed cell death loop and mouse mortality. Etanercept impaired the IAV-induced proinflammatory cytokine storm and lung injury. Our results highlight an additional mechanism involved in severe influenza that could be attenuated with clinically available therapies.