Genetic Resistance to Flaviviruses

Brinton, Margo A.

doi:10.1089/mab.2014.0009

Cited by 4 publications

(4 citation statements)

References 17 publications

(13 reference statements)

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“…On the other hand, RFs in the susceptible species likely lack certain binding sites and/or partners resulting in a relatively modest host response and disease development. Indeed, a more detailed study and comparison of specific RFs (such as TRIMs, IFITs, and oligoadenylate synthetase (OAS) [62–64] genes) in P . leucopus will provide information on any genetic variations and help us narrow down resistance determinant to specific genetic loci.…”

Section: Discussionmentioning

confidence: 99%

Interferon signaling in Peromyscus leucopus confers a potent and specific restriction to vector-borne flaviviruses

Izuogu

McNally²,

Harris

et al. 2017

PLoS ONE

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Tick-borne flaviviruses (TBFVs), including Powassan virus and tick-borne encephalitis virus cause encephalitis or hemorrhagic fevers in humans with case-fatality rates ranging from 1–30%. Despite severe disease in humans, TBFV infection of natural rodent hosts has little noticeable effect. Currently, the basis for resistance to disease is not known. We hypothesize that the coevolution of flaviviruses with their respective hosts has shaped the evolution of potent antiviral factors that suppress virus replication and protect the host from lethal infection. In the current study, we compared virus infection between reservoir host cells and related susceptible species. Infection of primary fibroblasts from the white-footed mouse (Peromyscus leucopus, a representative host) with a panel of vector-borne flaviviruses showed up to a 10,000-fold reduction in virus titer compared to control Mus musculus cells. Replication of vesicular stomatitis virus was equivalent in P. leucopus and M. musculus cells suggesting that restriction was flavivirus-specific. Step-wise comparison of the virus infection cycle revealed a significant block to viral RNA replication, but not virus entry, in P. leucopus cells. To understand the role of the type I interferon (IFN) response in virus restriction, we knocked down signal transducer and activator of transcription 1 (STAT1) or the type I IFN receptor (IFNAR1) by RNA interference. Loss of IFNAR1 or STAT1 significantly relieved the block in virus replication in P. leucopus cells. The major IFN antagonist encoded by TBFV, nonstructural protein 5, was functional in P. leucopus cells, thus ruling out ineffective viral antagonism of the host IFN response. Collectively, this work demonstrates that the IFN response of P. leucopus imparts a strong and virus-specific barrier to flavivirus replication. Future identification of the IFN-stimulated genes responsible for virus restriction specifically in P. leucopus will yield mechanistic insight into efficient control of virus replication and may inform the development of antiviral therapeutics.

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Section: Discussionmentioning

confidence: 99%

Interferon signaling in Peromyscus leucopus confers a potent and specific restriction to vector-borne flaviviruses

Izuogu

McNally²,

Harris

et al. 2017

PLoS ONE

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“…Canonically, Oas (oligoadenylate-synthetase) proteins exert their antiviral effect by activating latent cytosolic ribonuclease L (RNAse L), an enzyme that acts to degrade viral transcripts. Although Oas1b lacks this enzymatic activity, and therefore exerts antiviral activity through other, incompletely understood mechanisms, it has nevertheless been demonstrated to be protective against some flavivirus infections [ 58 , 59 , 60 , 61 ]. It was interesting to find that significantly higher expression of Oas1b occurred in the livers of infected deer mice as opposed to the kidneys and brains of infected hamsters ( Figure 4 ).…”

Section: Discussionmentioning

confidence: 99%

Increased Ifng and Il10 Expression Correlate with Disease in Rodent Models Experimentally Infected with Modoc Virus

Sherman

Petty

Schountz

et al. 2022

Viruses

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Flaviviruses present an ongoing threat to global public health, although the factors that contribute to the disease remain incompletely understood. We examined an acute Modoc virus (MODV) infection of two rodent models. Viral RNA was detected in the kidneys, spleen, liver, brain, urine, and sera of experimentally infected deer mice, a reservoir host of MODV, and Syrian hamsters, a known disease model. As expected, clinical outcomes differed between species, and the levels of viral RNA recovered from various tissues demonstrated signs of differential replication and tissue tropism. Multivariate analysis indicated significance in the profile of expressed genes between species when analyzed across tissues and over time (p = 0.02). Between-subject effects with corrected models revealed a significance specific to the expression of Ifng (p = 0.01). the expression of Ifng was elevated in hamsters as compared to deer mice in brain tissues at all timepoints. As the over-expression of Ifng has been shown to correlate with decreased vascular integrity, the findings presented here offer a potential mechanism for viral dissemination into the CNS. The expression of IL10 also differed significantly between species at certain timepoints in brain tissues; however, it is uncertain how increased expression of this cytokine may influence the outcome of MODV-induced pathology.

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“…Moreover, Flvrm, an oligoadenylate synthetase gene that potentially promotes resistance to flavivirus infection, appears to be present in some laboratory mice strains [ 165 , 166 ]. Mice that are susceptible to flavivirus infection tend to carry Flvs [ 167 , 168 ]. Flvr has been identified in wild mice and could, in part, aid in the elucidation of flavivirus persistence [ 169 ].…”

Section: Mechanisms Of Flavivirus Persistencementioning

confidence: 99%

Flavivirus Persistence in Wildlife Populations

Blahove

Carter

2021

Viruses

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A substantial number of humans are at risk for infection by vector-borne flaviviruses, resulting in considerable morbidity and mortality worldwide. These viruses also infect wildlife at a considerable rate, persistently cycling between ticks/mosquitoes and small mammals and reptiles and non-human primates and humans. Substantially increasing evidence of viral persistence in wildlife continues to be reported. In addition to in humans, viral persistence has been shown to establish in mammalian, reptile, arachnid, and mosquito systems, as well as insect cell lines. Although a considerable amount of research has centered on the potential roles of defective virus particles, autophagy and/or apoptosis-induced evasion of the immune response, and the precise mechanism of these features in flavivirus persistence have yet to be elucidated. In this review, we present findings that aid in understanding how vector-borne flavivirus persistence is established in wildlife. Research studies to be discussed include determining the critical roles universal flavivirus non-structural proteins played in flaviviral persistence, the advancement of animal models of viral persistence, and studying host factors that allow vector-borne flavivirus replication without destructive effects on infected cells. These findings underscore the viral–host relationships in wildlife animals and could be used to elucidate the underlying mechanisms responsible for the establishment of viral persistence in these animals.

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Genetic Resistance to Flaviviruses

Cited by 4 publications

References 17 publications

Interferon signaling in Peromyscus leucopus confers a potent and specific restriction to vector-borne flaviviruses

Interferon signaling in Peromyscus leucopus confers a potent and specific restriction to vector-borne flaviviruses

Increased Ifng and Il10 Expression Correlate with Disease in Rodent Models Experimentally Infected with Modoc Virus

Flavivirus Persistence in Wildlife Populations

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