TY - JOUR
T1 - TLR signaling controls lethal encephalitis in WNV-infected brain
AU - Sabouri, Amir H.
AU - Marcondes, Maria Cecilia Garibaldi
AU - Flynn, Claudia
AU - Berger, Michael
AU - Xiao, Nengming
AU - Fox, Howard S.
AU - Sarvetnick, Nora E.
N1 - Funding Information:
The authors thank Dr. Bruce Beutler, Dr. Xin Du, Kasper Hoebe, Marcie Kritzik, Mary Cleary, Patrick Secrest and Cody Fine for their help and constructive comments. The authors also thank Nikki Bortell (TSRI) for critically reading the manuscript. This is the manuscript number #22038 of the Scripps Research Institute.This work was funded by NIH U54 AI065359 and R21 DA 029491.
Publisher Copyright:
© 2014 Elsevier B.V. All rights reserved.
PY - 2014
Y1 - 2014
N2 - 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.
AB - 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.
KW - MyD88
KW - Toll-like receptors (TLRs)
KW - Trif
KW - West Nile virus
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U2 - 10.1016/j.brainres.2014.05.049
DO - 10.1016/j.brainres.2014.05.049
M3 - Article
C2 - 24928618
AN - SCOPUS:84926208636
SN - 0006-8993
VL - 1574
SP - 84
EP - 95
JO - Brain Research
JF - Brain Research
ER -