Separate sequences in a murine retroviral envelope protein mediate neuropathogenesis by complementary mechanisms with differing requirements for tumor necrosis factor alpha.
The innate immune response, through the induction of proinflammatory cytokines and antiviral factors, plays an important role in protecting the host from pathogens. Several components of the innate response, including tumor necrosis factor alpha (TNF-alpha), monocyte chemoattractant protein 1, interferon-inducible protein 10, and RANTES, are upregulated in the brain following neurovirulent retrovirus infection in humans and in animal models. However, it remains unclear whether this immune response is protective, pathogenic, or both. In the present study, by using TNF-alpha(-/-) mice we analyzed the contribution of TNF-alpha to neurological disease induced by four neurovirulent murine retroviruses, with three of these viruses encoding portions of the same neurovirulent envelope protein. Surprisingly, only one retrovirus (EC) required TNF-alpha for disease induction, and this virus induced less TNF-alpha expression in the brain than did the other retroviruses. Analysis of glial fibrillary acidic protein and F4/80 in EC-infected TNF-alpha(-/-) mice showed normal activation of astrocytes but not of microglia. Thus, TNF-alpha-mediated microglial activation may be important in the pathogenic process initiated by EC infection. In contrast, TNF-alpha was not required for pathogenesis of the closely related BE virus and the BE virus induced disease in TNF-alpha(-/-) mice by a different mechanism that did not require microglial activation. These results provide new insights into the multifactorial mechanisms involved in retrovirus-induced neurodegeneration and may also have analogies to other types of neurodegeneration.
Peterson
Karin E
KE
Department of Pathobiological Sciences, School of Veterinary Medicine, Skip Bertman Dr., Louisiana State University, Baton Rouge, LA 70803, USA. kpeterson@vetmed.lsu.edu
Hughes
Scott
S
Dimcheff
Derek E
DE
Wehrly
Kathy
K
Chesebro
Bruce
B
D000818:Animals; D001253:Astrocytes / Q000502:physiology / Q000821:virology; D008262:Macrophage Activation; D051379:Mice; D019636:Neurodegenerative Diseases / Q000209:etiology*; D012190:Retroviridae / Q000472:pathogenicity*; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*; D014759:Viral Envelope Proteins / Q000502:physiology*; D019562:Viral Load
D014409:Tumor Necrosis Factor-alpha; D014759:Viral Envelope Proteins