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

• Published in: Science immunology 2021-06, Vol.6 (60)
• Main Authors: Ghita, Luca, Spanier, Julia, Chhatbar, Chintan, Mulenge, Felix, Pavlou, Andreas, Larsen, Pia-Katharina, Waltl, Inken, Lueder, Yvonne, Kohls, Moritz, Jung, Klaus, Best, Sonja M, Förster, Reinhold, Stangel, Martin, Schreiner, Dietmar, Kalinke, Ulrich
• Format: Article
• Language: English
• Subjects: Adaptor Proteins, Vesicular Transport - genetics; Adaptor Proteins, Vesicular Transport - metabolism; Animals; CD8-Positive T-Lymphocytes - immunology; Chemokines - metabolism; Disease Models, Animal; Encephalitis, Viral - immunology; Encephalitis, Viral - pathology; Encephalitis, Viral - virology; Female; Humans; Male; Mice; Mice, Knockout; Myeloid Differentiation Factor 88 - genetics; Myeloid Differentiation Factor 88 - metabolism; Neurons - metabolism; Olfactory Bulb - cytology; Olfactory Bulb - immunology; Olfactory Bulb - pathology; Olfactory Bulb - virology; Rhabdoviridae Infections - immunology; Rhabdoviridae Infections - pathology; Rhabdoviridae Infections - virology; Signal Transduction - immunology; Vesiculovirus - immunology
• ISSN: 2470-9468; 2470-9468
• DOI: 10.1126/sciimmunol.abc9165

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.