Orchestration of antiviral responses within the infected central nervous system

Abstract

Many newly emerging and re-emerging viruses have neuroinvasive potential, underscoring viral encephalitis as a global research priority. Upon entry of the virus into the CNS, severe neurological life-threatening conditions may manifest that are associated with high morbidity and mortality. The currently available therapeutic arsenal against viral encephalitis is rather limited, emphasizing the need to better understand the conditions of local antiviral immunity within the infected CNS. In this review, we discuss new insights into the pathophysiology of viral encephalitis, with a focus on myeloid cells and CD8⁺ T cells, which critically contribute to protection against viral CNS infection. By illuminating the prerequisites of myeloid and T cell activation, discussing new discoveries regarding their transcriptional signatures, and dissecting the mechanisms of their recruitment to sites of viral replication within the CNS, we aim to further delineate the complexity of antiviral responses within the infected CNS. Moreover, we summarize the current knowledge in the field of virus infection and neurodegeneration and discuss the potential links of some neurotropic viruses with certain pathological hallmarks observed in neurodegeneration.

Keywords: Microglia activation; T cell recruitment to the brain; Virus control within the brain; Virus infection.

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]

Fig. 2

Detrimental inborn errors in virus sensing and IFN-I signaling illuminate relevant mechanisms of protection against viral encephalitis. Inborn errors of components of sensing pathways and IFN signaling important for protective innate immune responses during virus infection in the CNS that are described in this review are highlighted in bright colors. Mutations in the TLR3 gene were found in patients who presented with HSE [49] and VZV encephalitis [57], enterovirus rhombencephalitis [56], and influenza A virus-associated encephalitis [58]. Additionally, a TLR3 mutation was proposed as a TBE risk factor [59]. TLR3 is therefore critical for protective responses during viral encephalitis of multiple viral etiologies. TLR3 and other TLRs are trafficked and stabilized by UNC-93b [45, 47, 48]. UNC-93b deficiency has been detected in HSE patients [50]. Furthermore, HSE is associated with mutations in the TLR3 adapter molecule TRIF [54] and in the signaling molecules TRAF3 [53], TBK1 [52], IRF3 [51], and IRF7 [55]. A mutation in the RNA sensor MDA5 was identified in a child with EV71 rhombencephalitis [56]. Host rRNAs can trigger RIG-I activation [70]. TFIIA (GTF3A), a transcription factor for the RNA polymerase III complex, induces the transcription of rRNA, while SnoRNA31 (SNORA31 locus) is responsible for the pseudouridylation of rRNA. HSE is associated with mutations in both GTF3A [72] and SNORA31 [75], while missense mutations in RNA polymerase III are associated with severe VZV infections, including encephalitis [64]. Defective genes related to apoptosis and necrosis, such as RIPK3 [78], as well as genes connected to autophagy, including ATG4 and MAP1LC3B2 [79], have been shown to be associated with HSE. Several inborn errors in genes related to IFNAR signaling, including IFNAR1 [39], STAT1 [38], and IRF9 [40], are associated with HSE. IRF9 deficiency is further associated with multiple viral infections, including DENV and ZIKV [40]

Fig. 3

Chemokines derived from CNS-resident cells drive the recruitment of peripheral leukocytes into the infected brain. T cells are primed by DCs in secondary lymphoid organs in the periphery and proliferate [250]. Stromal cells (fibroblastic reticular cell-like cells surrounding the perivascular spaces and endothelial cells of the meningeal blood vessels) secrete CCL19 and CCL21, which recruit CCR7⁺ CD8⁺ T cells to the BBB. CXCL10 and CCL5 derived from neurons in the VSV model [30] or from astrocytes in the LCMV Traub model [143, 144] recruit T cells via CXCR3 and CCR5, respectively. CXCL10 is especially important for CXCR3⁺ CD8⁺ and gB⁺ CD8⁺ T cells [138, 139]. CXCR6 signaling leads to the maintenance of T cells in the CNS. Microglia interact with CD4⁺ and CD8⁺ T cells and activate previously primed antigen-specific T cells [29, 98, 250, 251]. Monocytes are recruited from the blood stream via the CCL2/CCL7–CCR2 axis [159], by CCL2 originating from neurons in the TMEV model [160]. CCR5 might contribute to leukocyte recruitment during WNV infection [145]