Toll-like receptor-2 exacerbates murine acute viral hepatitis.
Viral replication in the liver is generally detected by cellular endosomal Toll-like receptors (TLRs) and cytosolic helicase sensors that trigger antiviral inflammatory responses. Recent evidence suggests that surface TLR2 may also contribute to viral detection through recognition of viral coat proteins but its role in the outcome of acute viral infection remains elusive. In this study, we examined in vivo the role of TLR2 in acute infections induced by the highly hepatotrophic mouse hepatitis virus (MHV) type 3 and weakly hepatotrophic MHV-A59 serotype. To address this, C57BL/6 (wild-type; WT) and TLR2 knockout (KO) groups of mice were intraperitoneally infected with MHV3 or MHV-A59. MHV3 infection provoked a fulminant hepatitis in WT mice, characterized by early mortality and high alanine and aspartate transaminase levels, histopathological lesions and viral replication whereas infection of TLR2 KO mice was markedly less severe. MHV-A59 provoked a comparable mild and subclinical hepatitis in WT and TLR2 KO mice. MHV3-induced fulminant hepatitis in WT mice correlated with higher hepatic expression of interferon-β, interleukin-6, tumour necrosis factor-α, CXCL1, CCL2, CXCL10 and alarmin (interleukin-33) than in MHV-A59-infected WT mice and in MHV3-infected TLR2 KO mice. Intrahepatic recruited neutrophils, natural killer cells, natural killer T cells or macrophages rapidly decreased in MHV3-infected WT mice whereas they were sustained in MHV-A59-infected WT mice and MHV3-infected TLR2 KO. MHV3 in vitro infection of macrophagic cells induced rapid and higher viral replication and/or interleukin-6 induction in comparison to MHV-A59, and depended on viral activation of TLR2 and p38 mitogen-activated protein kinase. Taken together, these results support a new aggravating inflammatory role for TLR2 in MHV3-induced acute fulminant hepatitis.
Department of Biological Sciences, Université du Québec à Montréal, Montreal, Canada.
Christian
C
Bleau
Department of Biological Sciences, Université du Québec à Montréal, Montreal, Canada.
Mélanie
M
Burnette
U.1085 Inserm, IRSET, Institute of Research in Environmental and Occupational Health, Université de Rennes 1, Rennes, France.
Aveline
A
Filliol
U.1085 Inserm, IRSET, Institute of Research in Environmental and Occupational Health, Université de Rennes 1, Rennes, France.
Claire
C
Piquet-Pellorce
U.1085 Inserm, IRSET, Institute of Research in Environmental and Occupational Health, Université de Rennes 1, Rennes, France.
Michel
M
Samson
Department of Biological Sciences, Université du Québec à Montréal, Montreal, Canada.
Lucie
L
Lamontagne
D000208:Acute Disease; D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D005260:Female; D006524:Hepatitis, Viral, Animal / Q000276:immunology*; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D008264:Macrophages; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D006517:Murine hepatitis virus / Q000502:physiology*; D051195:Toll-Like Receptor 2 / Q000235:genetics / Q000378:metabolism*; D014779:Virus Replication / Q000235:genetics; D048051:p38 Mitogen-Activated Protein Kinases / Q000008:administration & dosage / Q000378:metabolism
D016207:Cytokines; D018836:Inflammation Mediators; C493486:Tlr2 protein, mouse; D051195:Toll-Like Receptor 2; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D048051:p38 Mitogen-Activated Protein Kinases
Toll-like receptor-2; coronavirus; inflammation; viral hepatitis