TLR signaling controls lethal encephalitis in WNV-infected brain

Amir H. Sabouri, Maria Cecilia Garibaldi Marcondes, Claudia Flynn, Michael Berger, Nengming Xiao, Howard S. Fox, Nora E. Sarvetnick

Research output: Contribution to journalArticle

11 Scopus citations

Abstract

Toll-like receptors (TLRs) are known to be activated in Central Nervous System (CNS) viral infections and are recognized to be a critical component in innate immunity. Several reports state a role for particular TLRs in various CNS viral infections. However, excessive TLR activation was previously reported by us in correlation with a pathogenic, rather than a protective, outcome, in a model of SIV encephalitis. Here we aimed at understanding the impact of TLR-mediated pathways by evaluating the early course of pathogenesis in the total absence of TLR signaling during CNS viral infections. We utilized a mouse model of sublethal West Nile virus (WNV) infection. WNV is an emerging neurotropic flavivirus, and a significant global cause of viral encephalitis. The virus was peripherally injected into animals that simultaneously lacked two key adapter molecules of TLR signaling, MyD88 and TRIF. On day 2 pi (post infection), MyD88/Trif-/-mice showed an increased susceptibility to WNV infection, and revealed an impairment in innate immune cytokines, when compared to wild type mice (WT). By day 6 pi, there was an increase in viral burden and robust expression of inflammatory cytokines as well as higher cell infiltration into the CNS in MyD88/Trif-/-, when compared to infected WT. A drastic increase in microglia activation, astrogliosis, and inflammatory trafficking were also observed on day 6 pi in MyD88/Trif-/- Our observations show a protective role for TLR signaling pathways in preventing lethal encephalitis at early stages of WNV infection.

Original languageEnglish (US)
Pages (from-to)84-95
Number of pages12
JournalBrain Research
Volume1574
DOIs
StatePublished - 2014

Keywords

  • MyD88
  • Toll-like receptors (TLRs)
  • Trif
  • West Nile virus

ASJC Scopus subject areas

  • Neuroscience(all)
  • Molecular Biology
  • Clinical Neurology
  • Developmental Biology

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