Journal article
Interferon signaling in Peromyscus leucopus confers a potent and specific restriction to vector-borne flaviviruses
PloS one, v 12(6), pp e0179781-e0179781
26 Jun 2017
PMID: 28650973
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
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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Details
- Title
- Interferon signaling in Peromyscus leucopus confers a potent and specific restriction to vector-borne flaviviruses
- Creators
- Adaeze O Izuogu - University of Toledo Medical CenterKristin L McNally - Innate Immunity and Pathogenesis Unit, Laboratory of Virology, Rocky Mountain Laboratories, DIR, NIAID, NIH, Hamilton, Montana, United States of AmericaStephen E Harris - The Graduate Center, CUNYBrian H Youseff - University of Toledo Medical CenterJohn B Presloid - University of Toledo Medical CenterChristopher Burlak - University of MinnesotaJason Munshi-South - Fordham UniversitySonja M Best - Innate Immunity and Pathogenesis Unit, Laboratory of Virology, Rocky Mountain Laboratories, DIR, NIAID, NIH, Hamilton, Montana, United States of AmericaR Travis Taylor - University of Toledo Medical Center
- Publication Details
- PloS one, v 12(6), pp e0179781-e0179781
- Publisher
- Public LIbrary of Science (PLOS)
- Grant note
- ZIA AI001125 / Intramural NIH HHS R15 GM099055 / NIGMS NIH HHS
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Biodiversity, Earth, and Environmental Science (BEES)
- Web of Science ID
- WOS:000404537300022
- Scopus ID
- 2-s2.0-85021255199
- Other Identifier
- 991021903954104721
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- Collaboration types
- Domestic collaboration
- Web of Science research areas
- Virology