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.
Highlights
Pathogen-associated molecular patterns (PAMPs) are molecular signatures of pathogens which facilitate induction of the host immune response [1,2]
We found that following influenza A virus (IAV) infection both human (U937 cells) (Figure 1A) and mouse [J774A.1 macrophage cell-line, primary alveolar macrophages and primary bone marrow-derived macrophages (BMDMs)] macrophages (Figure 1B–D) secreted high levels of S100A9
No cell death was observed during the 8–16 h postinfection period. These results demonstrated that following IAV infection, S100A9 is released to the extracellular environment from undamaged macrophages
Summary
Pathogen-associated molecular patterns (PAMPs) are molecular signatures of pathogens which facilitate induction of the host immune response [1,2]. PAMPs activate cellular pattern-recognition-receptors (PRRs) such as toll-like receptors (TLRs) to induce immunity [1,2]. Damage-associated molecular patterns (DAMPs), which are molecules produced from damaged or dead cells induce an inflammatory response in paracrine fashion via TLR activation [3]. We determined that during influenza A (IAV) virus infection, S100A9 protein ( known as Calgranulin B or MRP-14), which is classified as a DAMP, is released from undamaged infected cells to activate the TLR4/MyD88 pathway for induction of innate and inflammatory responses against IAV. We have identified extracellular S100A9 as a critical host-derived molecular pattern during IAV infection This protein has an essential role in enhancing the inflammatory response, which culminates in exacerbated IAV pathogenesis and lung disease
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