PMID- 24391503 OWN - NLM STAT- MEDLINE DCOM- 20150212 LR - 20211021 IS - 1553-7374 (Electronic) IS - 1553-7366 (Print) IS - 1553-7366 (Linking) VI - 10 IP - 1 DP - 2014 Jan TI - DAMP molecule S100A9 acts as a molecular pattern to enhance inflammation during influenza A virus infection: role of DDX21-TRIF-TLR4-MyD88 pathway. PG - e1003848 LID - 10.1371/journal.ppat.1003848 [doi] LID - e1003848 AB - 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. FAU - Tsai, Su-Yu AU - Tsai SY AD - Department of Microbiology and Immunology, The University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States of America. FAU - Segovia, Jesus A AU - Segovia JA AD - Department of Microbiology and Immunology, The University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States of America. FAU - Chang, Te-Hung AU - Chang TH AD - Department of Microbiology and Immunology, The University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States of America. FAU - Morris, Ian R AU - Morris IR AD - Department of Microbiology and Immunology, The University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States of America. FAU - Berton, Michael T AU - Berton MT AD - Department of Microbiology and Immunology, The University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States of America. FAU - Tessier, Philippe A AU - Tessier PA AD - Axe Maladies Infectieuses et Immunitaires, Centre de Recherche du CHU de Quebec, and Faculte de Medecine, Universite Laval, Quebec, Canada. FAU - Tardif, Melanie R AU - Tardif MR AD - Axe Maladies Infectieuses et Immunitaires, Centre de Recherche du CHU de Quebec, and Faculte de Medecine, Universite Laval, Quebec, Canada. FAU - Cesaro, Annabelle AU - Cesaro A AD - Axe Maladies Infectieuses et Immunitaires, Centre de Recherche du CHU de Quebec, and Faculte de Medecine, Universite Laval, Quebec, Canada. FAU - Bose, Santanu AU - Bose S AD - Department of Microbiology and Immunology, The University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States of America. LA - eng GR - R01 AI083387/AI/NIAID NIH HHS/United States GR - T32 DE014318/DE/NIDCR NIH HHS/United States GR - 8UL1 TR000149./TR/NCATS NIH HHS/United States GR - KL2 TR001118/TR/NCATS NIH HHS/United States GR - DE14318/DE/NIDCR NIH HHS/United States GR - UL1 TR000149/TR/NCATS NIH HHS/United States GR - UL1 TR001120/TR/NCATS NIH HHS/United States GR - AI083387/AI/NIAID NIH HHS/United States GR - P01 AI057986/AI/NIAID NIH HHS/United States GR - 84226/CAPMC/CIHR/Canada GR - AI057986/AI/NIAID NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20140102 PL - United States TA - PLoS Pathog JT - PLoS pathogens JID - 101238921 RN - 0 (Adaptor Proteins, Vesicular Transport) RN - 0 (Calgranulin B) RN - 0 (Myd88 protein, mouse) RN - 0 (Myeloid Differentiation Factor 88) RN - 0 (S100A9 protein, mouse) RN - 0 (TICAM-1 protein, mouse) RN - 0 (Tlr4 protein, mouse) RN - 0 (Toll-Like Receptor 4) RN - EC 2.7.7.- (DDX21 protein, mouse) RN - EC 3.6.4.13 (DEAD-box RNA Helicases) SB - IM MH - Adaptor Proteins, Vesicular Transport/genetics/*immunology MH - Animals MH - Calgranulin B/genetics/*immunology MH - DEAD-box RNA Helicases/genetics/*immunology MH - Dogs MH - Inflammation/genetics/immunology/pathology/virology MH - Influenza A Virus, H1N1 Subtype/*immunology MH - Madin Darby Canine Kidney Cells MH - Mice MH - Mice, Knockout MH - Myeloid Differentiation Factor 88/genetics/*immunology MH - Orthomyxoviridae Infections/genetics/*immunology/pathology MH - Signal Transduction/genetics/*immunology MH - Toll-Like Receptor 4/genetics/*immunology PMC - PMC3879357 COIS- The authors have declared that no competing interests exist. EDAT- 2014/01/07 06:00 MHDA- 2015/02/13 06:00 PMCR- 2014/01/02 CRDT- 2014/01/07 06:00 PHST- 2013/02/25 00:00 [received] PHST- 2013/11/08 00:00 [accepted] PHST- 2014/01/07 06:00 [entrez] PHST- 2014/01/07 06:00 [pubmed] PHST- 2015/02/13 06:00 [medline] PHST- 2014/01/02 00:00 [pmc-release] AID - PPATHOGENS-D-13-00524 [pii] AID - 10.1371/journal.ppat.1003848 [doi] PST - ppublish SO - PLoS Pathog. 2014 Jan;10(1):e1003848. doi: 10.1371/journal.ppat.1003848. Epub 2014 Jan 2.