Innate immune interactions within the central nervous system modulate pathogenesis of viral infections

Abstract

The innate immune system mediates protection against neurotropic viruses that replicate in the central nervous system (CNS). Virus infection within specific cells of the CNS triggers activation of several families of pattern recognition receptors including Toll-like receptors, retinoic acid-inducible gene I like receptors, nucleotide-binding oligomerization domain-like receptors, and cytosolic DNA sensors. In this review, we highlight recent advances in our understanding of how cell-intrinsic host defenses within the CNS modulate infection of different DNA and RNA viruses.

Figure 1. Antiviral signaling pathways in the CNS

Viruses can be detected by one of four classes of pathogen recognition receptors in cytoplasm or endosome of CNS cells: TLRs (e.g., TLR3 and TLR7), RLRs (e.g., RIG-I and MDA5), NLRs (e.g., NLRP3), or DNA sensors (e.g., cGAS). Engagement of dsRNA and ssRNA by TLR3 or TLR7 results in the respective activation of TRIF and MyD88 dependent signaling pathways to induce expression of proinflammatory cytokines and type I IFNs. RLR activation by viruses triggers MAVS-dependent signaling to activate the transcription factors IRF-3, IRF-7, and NF-κB to trigger expression of type I IFNs and immunomodulatory cytokines. Type I IFN binds to its receptor in an autocrine and paracrine manner and induces expression of hundreds of IFN-stimulated genes (ISGs) that inhibit different viral infections by a variety of mechanisms. As an example, PKR, RNase L, IFIT2, and viperin inhibit WNV infection in the CNS. PKR also confers antiviral effects via the autophagy pathway. SARM-1, which is activated by MAVS signaling, can induce neuronal apoptosis. cGAS detects DNA viruses and activates STING signaling pathways that lead to induction of IRF-3-dependent genes. Several miRNA can augment (miR-155/29b) or inhibit antiviral/inflammatory signaling (miR-132/146) or promote neuronal survival (miR-135). Finally, virus infection can activate the NLRP3 inflammasome through undefined pathogen associated molecular patterns, to trigger caspase-1 activation. This protease cleaves pro-IL-β generated by NF-κB signaling to its mature form, which is then secreted. Some of the IL-β antiviral signaling may be mediated by an IRF-1 transcriptional response.