Differential Role for TLR3 in Respiratory Syncytial Virus-Induced Chemokine Expression

Abstract

Respiratory syncytial virus (RSV) is the leading cause of lower respiratory tract infection in young infantsworldwide. Previous studies have reported that the induction of interleukin-8/CXCL8 and RANTES/CCL5 correlates with disease severity in humans. The production of these chemokines is elicited by viral replication and is NF-B dependent. RSV, a negative-sense single-stranded RNA virus, requires full-length positive-sense RNA for synthesis of new viral RNA. The aim of our studies was to investigate whether active viral replication by RSV could evoke chemokine production through TLR3-mediated signaling pathways. In TLR3-transfected HEK 293 cells, live RSV preferentially activated chemokines in both a time-and dose-dependent manner compared to vector controls. RSV was also shown to upregulate TLR3 in human lung fibroblasts and epithelial cells (MRC-5 and A549). Targeting the expression of TLR3 with small interfering RNA decreased synthesis of IP-10/CXCL10 and CCL5 but did not significantly reduce levels of CXCL8. Blocking the expression of the adapter protein MyD88 established a role for MyD88 in CXCL8 production, whereas CCL5 synthesis was found to be MyD88 independent. Production of CCL5 by RSV was induced directly through TLR3 signaling pathways and did not require interferon (IFN) signaling through the IFN-␣/␤ receptor. TLR3 did not affect viral replication, since equivalent viral loads were recovered from RSV-infected cells despite altered TLR3 expression. Taken together, our studies indicate that TLR3 mediates inflammatory cytokine and chemokine production in RSV-infected epithelial cells.

Endoplasmic reticulum stress and the unfolded protein response are linked to synergistic IFN‐β induction via X‐box binding protein 1

“…3A). To determine whether ER stress also augments cytoplasmic dsRNA-mediated induction of IFN-b, we took advantage of HEK293 cells that are unresponsive to exogenous poly(I:C) [32,33], but produce type I IFN following transfection [34]. Similar to the response to TLR4/3 agonists, there is strong synergistic IFN-b induction by transfected dsRNA in cells experiencing ER stress (Fig.…”

Toll-like receptor 3 regulates Mx expression in rare minnow Gobiocypris rarus after viral infection

“…They are evolutionarily conserved components and act as sentinels of the innate immune system, sensing a variety of ligands from lipopolysaccharide to flagellin to dsRNA by leucine-rich-repeat motifs (LRRs) in their extracellular domain (West et al 2006;Xu et al 2000;Ishii et al 2007). TLRs are type I transmembrane pattern recognition receptors (PRRs) that detect invading pathogens by binding conserved, microbially derived molecules (pathogen-associated molecular patterns, PAMPs) that are not found in higher eukaryotes, and that signal and induce expression of multiple host defense genes including proinflammatory cytokines and chemokines (Rudd et al 2005). TLRs are the focus of considerable attention as potential regulators and controllers of the immune response through their ability to recognize PAMPs, and are arousing interest as potential targets for the development of new therapies for multiple diseases (Zuany-Amorim et al 2002).…”

Essential role of mda-5 in type I IFN responses to polyriboinosinic:polyribocytidylic acid and encephalomyocarditis picornavirus

“…TRIF also triggers a signaling cascade that activates NF-B and the transcription of proinflammatory cytokine genes (2). The TLR3 pathway has been implicated in the host responses to respiratory syncytial virus and influenza A virus infections in vitro (14,15) and West Nile virus and murine cytomegalovirus (MCMV) infections in vivo (7,16). However, additional in vivo studies with lymphocytic choriomeningitis virus, reovirus, and MCMV have indicated that antiviral responses are also mediated by pathways independent of TLR3 (17,18).…”