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

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. © 2014 tsai et al.