Differential role for TLR3 in respiratory syncytial virus-induced chemokine expression.
Respiratory syncytial virus (RSV) is the leading cause of lower respiratory tract infection in young infants worldwide. 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-kappaB 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-alpha/beta 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.
Rudd
Brian D
BD
Department of Pathology, University of Michigan Medical School, 1301 Catherine St., 5214 Medical Science 1, Ann Arbor, MI 48109, USA.
Burstein
Ezra
E
Duckett
Colin S
CS
Li
Xiaoxia
X
Lukacs
Nicholas W
NW
D048868:Adaptor Proteins, Signal Transducing; D000943:Antigens, Differentiation / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D018946:Chemokine CCL5; D054357:Chemokine CXCL10; D054370:Chemokine CXCL9; D018925:Chemokines / Q000096:biosynthesis*; D019742:Chemokines, CC / Q000096:biosynthesis; D019743:Chemokines, CXC / Q000096:biosynthesis; D004847:Epithelial Cells / Q000821:virology; D005347:Fibroblasts / Q000821:virology; D005786:Gene Expression Regulation; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis; D007372:Interferons / Q000276:immunology; D008562:Membrane Glycoproteins / Q000276:immunology*; D053594:Myeloid Differentiation Factor 88; D011956:Receptors, Cell Surface / Q000276:immunology*; D011971:Receptors, Immunologic / Q000187:drug effects / Q000502:physiology; D012136:Respiratory Syncytial Viruses / Q000276:immunology*; D051196:Toll-Like Receptor 3; D051193:Toll-Like Receptors; D014779:Virus Replication / Q000276:immunology
D048868:Adaptor Proteins, Signal Transducing; D000943:Antigens, Differentiation; C483024:CCL5 protein, human; C114753:CXCL10 protein, human; C080810:CXCL9 protein, human; D018946:Chemokine CCL5; D054357:Chemokine CXCL10; D054370:Chemokine CXCL9; D018925:Chemokines; D019742:Chemokines, CC; D019743:Chemokines, CXC; D036341:Intercellular Signaling Peptides and Proteins; C507779:MYD88 protein, human; D008562:Membrane Glycoproteins; D053594:Myeloid Differentiation Factor 88; D011956:Receptors, Cell Surface; D011971:Receptors, Immunologic; C495344:TLR3 protein, human; D051196:Toll-Like Receptor 3; D051193:Toll-Like Receptors; D007372:Interferons
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