MyD88 signaling by neurons induces chemokines that recruit protective leukocytes to the virus-infected CNS

Abstract

During viral CNS infection, MyD88 signaling in infected neurons orchestrates recruitment of protective peripheral immune cells. Encephalitis protection Viral encephalitis is caused by infection of the CNS by neurotropic viruses and can result in long-term neurological complications or death. Ghita et al. studied the role of the innate immune signaling adapter myeloid differentiation primary response gene 88 (MyD88) in a vesicular stomatitis virus (VSV) murine model of CNS infection. MyD88 is a signaling adapter for TLR and IL-1 receptor signaling. Here, they observed that MyD88 was required for recruitment of leukocytes to the CNS, especially CD8 T cells, and it was critical for protection against death. MyD88 signaling in neurons was needed for chemokine production and leukocyte recruitment to the CNS, and together, these findings provide insight into innate immune mechanisms involved in protection against viral encephalitis. Viral encephalitis initiates a series of immunological events in the brain that can lead to brain damage and death. Astrocytes express IFN-β in response to neurotropic infection, whereas activated microglia produce proinflammatory cytokines and accumulate at sites of infection. Here, we observed that neurotropic vesicular stomatitis virus (VSV) infection causes recruitment of leukocytes into the central nervous system (CNS), which requires MyD88, an adaptor of Toll-like receptor and interleukin-1 receptor signaling. Infiltrating leukocytes, and in particular CD8+ T cells, protected against lethal VSV infection of the CNS. Reconstitution of MyD88, specifically in neurons, restored chemokine production in the olfactory bulb as well as leukocyte recruitment into the infected CNS and enhanced survival. Comparative analysis of the translatome of neurons and astrocytes verified neurons as the critical source of chemokines, which regulated leukocyte infiltration of the infected brain and affected survival.