Keeping it in check: chronic viral infection and antiviral immunity in the brain

Abstract

It is becoming clear that the manner by which the immune response resolves or contains infection by a pathogen varies according to the tissue that is affected. Unlike many peripheral cell types, CNS neurons are generally non-renewable. Thus, the cytolytic and inflammatory strategies that are effective in controlling infections in the periphery could be damaging if deployed in the CNS. Perhaps for this reason, the immune response to some CNS viral infections favours maintenance of neuronal integrity and non-neurolytic viral control. This modified immune response — when combined with the unique anatomy and physiology of the CNS — provides an ideal environment for the maintenance of viral genomes, including those of RNA viruses. Therefore, it is possible that such viruses can reactivate long after initial viral exposure, contributing to CNS disease.

Within host RNA virus persistence: mechanisms and consequences

“…Long-recognized examples include hepatocellular carcinoma and liver fibrosis as a late consequence of HCV infection [18], and SSPE following measles virus infection. Indeed, the CNS, as an immunologically privileged site (see below), is an organ in which RNA viruses can often establish persistent infections with disease consequences [5,19]. Recent examples include reactivation of CNS infection after apparent recovery from Ebola virus disease [14,20].…”

Intercellular Communication Is Key for Protective IFNα/β Signaling During Viral Central Nervous System Infection

“…Low but constitutive expression of IFNa/bs and their homeostatic activity in the CNS implied that CNS-resident cells are prepared to rapidly induce protective IFN responses. Moreover, high susceptibility of IFNAR -/mice to neurotropic viruses highlights the essential role of IFNAR for protection (26,38). As plasmacytoid DCs, potent peripheral IFNa/b inducers, are absent from the brain parenchyma, resident CNS cells rely on intrinsic induction of IFNa/b (4,38).…”

“…However, they differ widely in both the repertoire and magnitude of basal and inducible transcripts encoding PRRs and factors associated with the IFNa/b pathway, including the receptor chains IFNAR1 and IFNAR2, as well as STAT1 (16,22,28,35,46,48). Responses can even be different within neuronal cell subtypes (6,26). Nevertheless the rapid induction of genes involved in pathogen sensing and their signaling components by the positive IFNAR signaling feedback loop assures that poor IFNa/b inducer cells nevertheless make vital contributions to overall innate antiviral protection (26,28,53).…”

“…Responses can even be different within neuronal cell subtypes (6,26). Nevertheless the rapid induction of genes involved in pathogen sensing and their signaling components by the positive IFNAR signaling feedback loop assures that poor IFNa/b inducer cells nevertheless make vital contributions to overall innate antiviral protection (26,28,53). However, the interdependence of CNS cells in optimizing protective IFNa/b function requires further investigation.…”

“…Many neurotropic viruses infect neurons as primary targets, but glia cells are also susceptible (26,38,41). Immune inflammatory responses to clear virus infection must therefore be tightly regulated to minimize direct viral as well as immune-mediated damage to neurons; the inability to achieve an appropriate balance manifests in breakdown of neuronal function and even mortality (26,41). A rapid but delicately orchestrated innate immune response tailored for each infection is thus critical to limit early virus replication and spread, ultimately tipping the balance in favor of subsequent control by adaptive immune effector cells.…”