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(American Journal of Pathology. 2005;166:1419-1426.)
© 2005 American Society for Investigative Pathology

Lethal Encephalitis in Myeloid Differentiation Factor 88-Deficient Mice Infected with Herpes Simplex Virus 1

Daniel S. Mansur*, Erna G. Kroon*, Maurício L. Nogueira{dagger}, Rosa M.E. Arantes{ddagger}, Soraia C.O. Rodrigues§, Shizuo Akira||, Ricardo T. Gazzinelli§ and Marco A. Campos§

From the Departamentoes de Microbiologia,* Patologia,{ddagger} and Bioquímica e Imunologia, Universidade Federal de Minas Gerais, Belo Horizonte; the Centro de Pesquisas René Rachou,§ Fundação Oswaldo Cruz, Belo Horizonte, Brasil; the Laboratory of Viral Diseases,{dagger} National Institute of Allergy and Infectious Disease, National Institutes of Health, Bethesda, Maryland; and the Department of Host Defense,|| Research Institute for Microbial Diseases, Osaka University, Osaka, Japan

Herpes simplex virus 1 (HSV-1), a large DNA virus from the Herpesviridae family, is the major cause of sporadic lethal encephalitis and blindness in humans. Recent studies have shown the importance of Toll-like receptors (TLRs) in the immune response to HSV-1 infection. Myeloid differentiation factor 88 (MyD88) is a critical adaptor protein that is downstream to mediated TLR activation and is essential for the production of inflammatory cytokines. Here, we studied the relationship between MyD88 and HSV-1 using a purified HSV-1 isolated from a natural oral recurrent human infection. We observed the activation of TLR-2 by HSV-1 in vitro using Chinese hamster ovary cells stably transfected with a reporter gene. Interestingly, we found that only peritoneal macrophages from MyD88–/– mice, but not macrophages from TRL2–/– or from wild-type mice, were unable to produce tumor necrosis factor-{alpha} in response to HSV-1 exposure. Additionally, although TLR2–/– mice showed no enhanced susceptibility to intranasal infection with HSV-1, MyD88–/– mice were highly susceptible to infection and displayed viral migration to the brain, severe neuropathological signs of encephalitis, and 100% mortality by day 10 after infection. Together, our results suggest that innate resistance to HSV-1 is mediated by MyD88 and may rely on activation of multiple TLRs.





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