title: The innate immune adaptor molecule MyD88 restricts West Nile virus replication and spread in neurons of the central nervous system.
abstract: Type I interferons (IFN-α/β) control viral infection by triggering the expression of genes that restrict transcription, translation, replication, and assembly. Many viruses induce IFN responses after recognition by cytoplasmic or endosomal RNA sensors (RIG-I-like RNA helicases [RLR] and Toll-like receptors [TLR]), which signal through the cognate adaptor signaling molecules IPS-1, TRIF, and MyD88. Recent studies have demonstrated that IPS-1-dependent induction of IFN-α/β downstream of RLR recognition restricts West Nile virus (WNV) infection in many cell types, whereas TRIF-dependent TLR3 signaling limits WNV replication in neurons. Here, we examined the contribution of MyD88 signaling to the control of WNV by evaluating IFN induction and virus replication in genetically deficient cells and mice. MyD88(-/-) mice showed increased lethality after WNV infection and elevated viral burden primarily in the brain, even though little effect on the systemic type I IFN response was observed. Intracranial inoculation studies corroborated these findings, as WNV spread more rapidly in the central nervous system of MyD88(-/-) mice, and this phenotype preceded the recruitment of inflammatory leukocytes. In vitro, increased WNV replication was observed in MyD88(-/-) macrophages and subsets of neurons but not in myeloid dendritic cells. MyD88 had an independent effect on recruitment of monocyte-derived macrophages and T cells into the brain that was associated with blunted induction of the chemokines that attract leukocytes. Our experiments suggest that MyD88 restricts WNV by inhibiting replication in subsets of cells and modulating expression of chemokines that regulate immune cell migration into the central nervous system.
authors.affiliation: Department of Medicine, Washington University School of Medicine, St Louis, Missouri 63110, USA.
authors.forename: Kristy J
authors.initials: KJ
authors.lastname: Szretter
authors.forename: Stephane
authors.initials: S
authors.lastname: Daffis
authors.forename: Jigisha
authors.initials: J
authors.lastname: Patel
authors.forename: Mehul S
authors.initials: MS
authors.lastname: Suthar
authors.forename: Robyn S
authors.initials: RS
authors.lastname: Klein
authors.forename: Michael
authors.initials: M
authors.lastname: Gale
authors.forename: Michael S
authors.initials: MS
authors.lastname: Diamond
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002490:Central Nervous System / Q000821:virology*; D018925:Chemokines / Q000378:metabolism; D017931:DNA Primers / Q000235:genetics; D005786:Gene Expression Regulation / Q000276:immunology; D007150:Immunohistochemistry; D007370:Interferon Type I / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics*; D009474:Neurons / Q000821:virology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D018709:Statistics, Nonparametric; D014779:Virus Replication / Q000276:immunology*; D014901:West Nile Fever / Q000276:immunology* / Q000503:physiopathology; D014902:West Nile virus / Q000276:immunology*
chemical_list: D018925:Chemokines; D017931:DNA Primers; D007370:Interferon Type I; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88