Interferon Control of Neurotropic Viral Infections

Milora, Katelynn A.; Rall, Glenn F.

doi:10.1016/j.it.2019.07.005

Cited by 6 publications

(3 citation statements)

References 85 publications

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“…Recovery from infection requires non-cytolytic clearance of the virus from the CNS to avoid further damage to tissue ( Griffin and Metcalf, 2011 ). B cell production of antiviral antibodies ( Bartlett and Griffin, 2020 ), T cell production of IFN-γ ( Milora and Rall, 2019 ), and other immune responses within the infected nervous system are important for non-cytolytic clearance of infectious virus and viral RNA and also for prevention of viral reactivation and recrudescence ( Manglani and McGavern, 2018 ). Microglia and other neural cells exert direct antiviral effects by producing type I interferons that consequently induce autocrine and paracrine expression of IFN-stimulated genes (ISGs), resulting in viral control and hardening of neural cell susceptibility to further infection ( Chen et al, 2019 ).…”

Section: Central Nervous System-specific Consequences Of Viral Infectionmentioning

confidence: 99%

Molecular Mechanisms in the Genesis of Seizures and Epilepsy Associated With Viral Infection

Löscher

Howe

2022

Front. Mol. Neurosci.

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Seizures are a common presenting symptom during viral infections of the central nervous system (CNS) and can occur during the initial phase of infection (“early” or acute symptomatic seizures), after recovery (“late” or spontaneous seizures, indicating the development of acquired epilepsy), or both. The development of acute and delayed seizures may have shared as well as unique pathogenic mechanisms and prognostic implications. Based on an extensive review of the literature, we present an overview of viruses that are associated with early and late seizures in humans. We then describe potential pathophysiologic mechanisms underlying ictogenesis and epileptogenesis, including routes of neuroinvasion, viral control and clearance, systemic inflammation, alterations of the blood-brain barrier, neuroinflammation, and inflammation-induced molecular reorganization of synapses and neural circuits. We provide clinical and animal model findings to highlight commonalities and differences in these processes across various neurotropic or neuropathogenic viruses, including herpesviruses, SARS-CoV-2, flaviviruses, and picornaviruses. In addition, we extensively review the literature regarding Theiler’s murine encephalomyelitis virus (TMEV). This picornavirus, although not pathogenic for humans, is possibly the best-characterized model for understanding the molecular mechanisms that drive seizures, epilepsy, and hippocampal damage during viral infection. An enhanced understanding of these mechanisms derived from the TMEV model may lead to novel therapeutic interventions that interfere with ictogenesis and epileptogenesis, even within non-infectious contexts.

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Section: Central Nervous System-specific Consequences Of Viral Infectionmentioning

confidence: 99%

Molecular Mechanisms in the Genesis of Seizures and Epilepsy Associated With Viral Infection

Löscher

Howe

2022

Front. Mol. Neurosci.

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“…However, not all cell types are equally susceptible to viral infection, with differential CNS cell types adopting distinct antiviral strategies to defend against viral infection within its own microenvironment, which defines the outcome of the viral infection. In this context, although glial cells are major type I IFN producers and responders due to their stronger expression of STAT and ISG repertoires, astrocytes tend to adopt a more responsive role with microglial cells being more productive, and potentially acting as an alarming signal for adaptive immunity, driving major anti-inflammatory roles during viral infection ( 111 ). In contrast, neurons may respond differentially to type I IFN based on their maturity state or brain region they are located in, which may define their ISG repertoire and the relative alterations in ISGs expression in response to IFNs; with further work in the field required to fully understand the role of autophagy induction in preference to ISG upregulation to inhibit viral spread and minimize further damage to non-renewable neurons.…”

Section: Conclusion and Future Perspectivesmentioning

confidence: 99%

Antiviral response within different cell types of the CNS

et al. 2022

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The central nervous system (CNS) is a constitutive structure of various cell types conserved by anatomical barriers. Many of the major CNS cell-type populations distributed across the different brain regions are targets for several neurotropic viruses. Numerous studies have demonstrated that viral susceptibility within the CNS is not absolute and initiates a cell-type specific antiviral defence response. Neurons, astrocytes, and microglial cells are among the major resident cell populations within the CNS and are all equipped to sense viral infection and induce a relative antiviral response mostly through type I IFN production, however, not all these cell types adopt a similar antiviral strategy. Rising evidence has suggested a diversity regarding IFN production and responsiveness based on the cell type/sub type, regional distinction and cell`s developmental state which could shape distinct antiviral signatures. Among CNS resident cell types, neurons are of the highest priority to defend against the invading virus due to their poor renewable nature. Therefore, infected and uninfected glial cells tend to play more dominant antiviral roles during a viral infection and have been found to be the major CNS IFN producers. Alternatively, neuronal cells do play an active part during antiviral responses but may adopt differential strategies in addition to induction of a typical type I IFN response, to minimize the chance of cellular damage. Heterogeneity observed in neuronal IFN responsiveness may be partially explained by their altered ISGs and/or lower STATS expression levels, however, further in vivo studies are required to fully elucidate the specificity of the acquired antiviral responses by distinct CNS cell types.

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“…In 2022, local transmission of JEV was detected in Australia for the first time since 1995 and ultimately led to dozens of reported JEV cases within Australia(43). In North America, responses(49)(50)(51)(52). The pathogenic mechanisms of neuroinvasive flaviviruses have been studied extensively in mice, which recapitulate key features of human disease such as neuronal infection, immune infiltration into the CNS, paralysis, encephalitis, and cognitive loss.…”

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confidence: 99%

Neuroinvasive flavivirus pathogenesis is restricted by host genetic factors in Collaborative Cross mice, independently of Oas1b

Jasperse¹,

Mattocks²,

Noll

et al. 2022

Preprint

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Powassan virus (POWV) is an emerging tick-borne flavivirus that causes neuroinvasive disease, including encephalitis, meningitis, and paralysis. Similar to other neuroinvasive flaviviruses, such as West Nile virus (WNV) and Japanese encephalitis virus (JEV), POWV disease presentation is heterogeneous, and the factors influencing disease outcome are not fully understood. We used Collaborative Cross (CC) mice to assess the impact of host genetic factors on POWV pathogenesis. We infected a panel of Oas1b-null CC lines with POWV and observed a range of susceptibility phenotypes, indicating that host factors other than the well-characterized flavivirus restriction factor Oas1b modulate POWV pathogenesis in CC mice. Among Oas1b-null CC lines, we identified multiple highly susceptible lines (0% survival), including CC071, and a single resistant line (78% survival), CC045. Susceptibility phenotypes generally were concordant among neuroinvasive flaviviruses, although we identified one line, CC006, that was resistant specifically to JEV, suggesting that both pan-flavivirus and virus-specific mechanisms contribute to susceptibility phenotypes in CC mice. We found that POWV replicated to higher titers in bone marrow-derived macrophages from CC071 mice compared to CC045 mice, suggesting that resistance could result from cell-intrinsic restriction of viral replication. Although serum viral loads at 2 days post-infection were equivalent between CC071 and CC045 mice, clearance of POWV from the serum was significantly slower in CC071 mice. Furthermore, CC045 mice had significantly lower viral loads in the brain at 7 days post-infection compared to CC071 mice, suggesting that reduced CNS infection contributes to the resistant phenotype of CC045 mice.

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Interferon Control of Neurotropic Viral Infections

Cited by 6 publications

References 85 publications

Molecular Mechanisms in the Genesis of Seizures and Epilepsy Associated With Viral Infection

Molecular Mechanisms in the Genesis of Seizures and Epilepsy Associated With Viral Infection

Antiviral response within different cell types of the CNS

Neuroinvasive flavivirus pathogenesis is restricted by host genetic factors in Collaborative Cross mice, independently of Oas1b

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