title: DAMP molecule S100A9 acts as a molecular pattern to enhance inflammation during influenza A virus infection: role of DDX21-TRIF-TLR4-MyD88 pathway.
abstract: 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.
authors.affiliation: Department of Microbiology and Immunology, The University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States of America.
authors.forename: Su-Yu
authors.initials: SY
authors.lastname: Tsai
authors.affiliation: Department of Microbiology and Immunology, The University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States of America.
authors.forename: Jesus A
authors.initials: JA
authors.lastname: Segovia
authors.affiliation: Department of Microbiology and Immunology, The University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States of America.
authors.forename: Te-Hung
authors.initials: TH
authors.lastname: Chang
authors.affiliation: Department of Microbiology and Immunology, The University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States of America.
authors.forename: Ian R
authors.initials: IR
authors.lastname: Morris
authors.affiliation: Department of Microbiology and Immunology, The University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States of America.
authors.forename: Michael T
authors.initials: MT
authors.lastname: Berton
authors.affiliation: Axe Maladies Infectieuses et Immunitaires, Centre de Recherche du CHU de Québec, and Faculté de Médecine, Université Laval, Quebec, Canada.
authors.forename: Philippe A
authors.initials: PA
authors.lastname: Tessier
authors.affiliation: Axe Maladies Infectieuses et Immunitaires, Centre de Recherche du CHU de Québec, and Faculté de Médecine, Université Laval, Quebec, Canada.
authors.forename: Mélanie R
authors.initials: MR
authors.lastname: Tardif
authors.affiliation: Axe Maladies Infectieuses et Immunitaires, Centre de Recherche du CHU de Québec, and Faculté de Médecine, Université Laval, Quebec, Canada.
authors.forename: Annabelle
authors.initials: A
authors.lastname: Cesaro
authors.affiliation: Department of Microbiology and Immunology, The University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States of America.
authors.forename: Santanu
authors.initials: S
authors.lastname: Bose
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000235:genetics / Q000276:immunology*; D000818:Animals; D040502:Calgranulin B / Q000235:genetics / Q000276:immunology*; D053487:DEAD-box RNA Helicases / Q000235:genetics / Q000276:immunology*; D004285:Dogs; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000821:virology; D053118:Influenza A Virus, H1N1 Subtype / Q000276:immunology*; D061985:Madin Darby Canine Kidney Cells; D051379:Mice; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000276:immunology*; D009976:Orthomyxoviridae Infections / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000276:immunology*
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D040502:Calgranulin B; D053487:DEAD-box RNA Helicases; D053594:Myeloid Differentiation Factor 88; D051197:Toll-Like Receptor 4; C507780:Myd88 protein, mouse; C576329:S100A9 protein, mouse; C476286:Ticam1 protein, mouse; C493487:Tlr4 protein, mouse; C528957:DDX21 protein, mouse