DAMP Molecule S100A9 Acts as a Molecular Pattern to Enhance Inflammation during Influenza A Virus Infection: Role of DDX21-TRIF-TLR4-MyD88 Pathway

PLoS Pathogens

Mélanie R. Tardif¹  Annabelle Cesaro¹  Philippe A. Tessier¹  Santanu Bose²  Te-Hung Chang²  Su-Yu Tsai²  Ian R. Morris²  Michael T. Berton²  Jesus A. Segovia² 

[1] Axe Maladies Infectieuses et Immunitaires, Centre de Recherche du CHU de Québec, and Faculté de Médecine, Université Laval, Quebec, Canada;Department of Microbiology and Immunology, The University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States of America

关键词: Influenza A virus;    Apoptosis;    Enzyme-linked immunoassays;    Macrophages;    Antibodies;    Inflammatory diseases;    Reverse transcriptase-polymerase chain reaction;    Routes of administration;   

DOI  :  10.1371/journal.ppat.1003848

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

Pathogen-associated molecular patterns (PAMPs) trigger host immune response by activating pattern recognition receptors like toll-like receptors (TLRs). However, the mechanism whereby several pathogens, including viruses, activate TLRs via a non-PAMP mechanism is unclear. Endogenous “inflammatory mediators” called damage-associated molecular patterns (DAMPs) have been implicated in regulating immune response and inflammation. However, the role of DAMPs in inflammation/immunity during virus infection has not been studied. We have identified a DAMP molecule, S100A9 (also known as Calgranulin B or MRP-14), as an endogenous non-PAMP activator of TLR signaling during influenza A virus (IAV) infection. S100A9 was released from undamaged IAV-infected cells and extracellular S100A9 acted as a critical host-derived molecular pattern to regulate inflammatory response outcome and disease during infection by exaggerating pro-inflammatory response, cell-death and virus pathogenesis. Genetic studies showed that the DDX21-TRIF signaling pathway is required for S100A9 gene expression/production during infection. Furthermore, the inflammatory activity of extracellular S100A9 was mediated by activation of the TLR4-MyD88 pathway. Our studies have thus, underscored the role of a DAMP molecule (i.e. extracellular S100A9) in regulating virus-associated inflammation and uncovered a previously unknown function of the DDX21-TRIF-S100A9-TLR4-MyD88 signaling network in regulating inflammation during infection.

【 授权许可】

CC BY