Lethal encephalitis in myeloid differentiation factor 88-deficient mice infected with herpes simplex virus 1.
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.
Mansur
Daniel S
DS
Departamento de Microbiologia, Universidade Federal de Minas Gerais, Belo Horizonte, Brasil.
Kroon
Erna G
EG
Nogueira
Maurício L
ML
Arantes
Rosa M E
RM
Rodrigues
Soraia C O
SC
Akira
Shizuo
S
Gazzinelli
Ricardo T
RT
Campos
Marco A
MA
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D000943:Antigens, Differentiation; D016466:CHO Cells; D002522:Chlorocebus aethiops; D006224:Cricetinae; D003412:Cricetulus; D004198:Disease Susceptibility; D004660:Encephalitis / Q000378:metabolism* / Q000401:mortality / Q000821:virology*; D006561:Herpes Simplex / Q000209:etiology; D018259:Herpesvirus 1, Human; D007371:Interferon-gamma / Q000172:deficiency; D051379:Mice; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88; D011971:Receptors, Immunologic / Q000172:deficiency* / Q000378:metabolism; D051195:Toll-Like Receptor 2; D014709:Vero Cells
D048868:Adaptor Proteins, Signal Transducing; D000943:Antigens, Differentiation; C507779:MYD88 protein, human; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D011971:Receptors, Immunologic; C493486:Tlr2 protein, mouse; D051195:Toll-Like Receptor 2; D007371:Interferon-gamma