MyD88 expressing T cells are required for neuropathogenesis of Tacaribe virus.

Immune responses play a key role in the pathogenesis of viral encephalitis. Infection of neonatal C57Bl/6 (B6) mice with neurotropic arenavirus Tacaribe (TCRV) results in encephalitis, paralysis and death within 15 days of challenge. Analysis of the expression of 96 immune related genes using a mouse Taqman Low Density Array (TLDA) showed a strong inflammatory response in the brain characterized by high levels of inflammatory chemokines, mainly CXCL10/IP-10, IL1β, Granzyme, IFNγ and TNFα and T cell infiltration. In contrast, CD3ϵ-/- mice which lack T cells (CD3ϵKO) show 100% survival and minimal inflammatory response despite having similar viral loads in the brain. Transfer of either CD4+ or CD8+ T cells from B6 to CD3ϵKO mice resulted in encephalitis and death. Disease was independent of TLR2, 3, 7 or 9, whereas 90% of MyD88-/- mice survived challenge. Brains of MyD88-/- mice showed minimal inflammation and T cell infiltration but had reduced viral titers when compared to B6 or CD3ϵKO mice. MYD88 does not directly affect TCRV replication since infection of B6 and MYD88-/- primary neuro cultures in vitro rendered similar virus titers. However, T cells from MyD88-/- mice were unable to mediate encephalitis when transferred to infected CD3ϵKO. These data show that T cells mediate disease and death in TCRV infected neonates without affecting viral replication and brain tropism and suggest a critical role of MYD88 expression on T cell in the pathology.