Fig. 1

Schematic depiction of the sequence of immunological events triggered upon CNS virus infection. (1) Upon virus entry into the CNS, IFN-I signaling is essential for restricting virus propagation and promoting host survival. Astrocytes are important IFN-I producers, and together with neurons, they regulate the activation of microglia in an IFNAR1-independent manner [24, 25]. Microglial activation and recruitment to sites of infection are essential for virus control within the infected CNS [27, 29]. (2) Productive virus replication is established mainly within neuronal cells, leading to the induction of a potent chemokine response, which is tightly regulated by MyD88 signaling in a neuron-specific manner [30, 138]. Neuronal chemokine responses drive T-cell and monocytic cell recruitment to the infected CNS, which critically affects the outcome of the infection [30]. (3) At sites of infection, microglia are activated and proliferate, and they cross-present antigens to antigen-specific T cells within the infected CNS [29]. Infiltrated antigen-specific T cells are locally relicensed by microglia to exhibit optimal cytolytic activity that causes minimal tissue damage [29, 152]. However, under certain conditions, T-cell restimulation by microglia can lead to elimination of synapses and cognitive decline upon viral clearance from the CNS [120, 179]