Epigenetic Suppression of Interferon Lambda Receptor Expression Leads to Enhanced Human Norovirus Replication In Vitro.
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American Society for Microbiology
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Arthur, S. E., Sorgeloos, F., Hosmillo, M., & Goodfellow, I. (2019). Epigenetic Suppression of Interferon Lambda Receptor Expression Leads to Enhanced Human Norovirus Replication In Vitro.. mBio, 10 (5)https://doi.org/10.1128/mBio.02155-19
Human norovirus (HuNoV) is the main cause of gastroenteritis worldwide yet no therapeutics are currently available. Here, we utilize a human norovirus replicon in human gastric tumor (HGT) cells to identify host factors involved in promoting or inhibiting HuNoV replication. We observed that an IFN-cured population of replicon-harboring HGT cells (HGT-cured) was enhanced in their ability to replicate transfected HuNoV RNA compared to parental HGT cells, suggesting that differential gene expression in HGT-cured cells created an environment favouring norovirus replication. Microarrays were used to identify genes differentially regulated in HGT-NV and HGT-cured compared to parental cells. We found that IFN lambda receptor (IFNLR1) expression was highly reduced in HGT-NV and HGT-cured cells. While all three cell lines responded to exogenous IFN-β by inducing interferon-stimulated genes, HGT-NV and HGT-cured cells failed to respond to exogenous IFN-λ. Methylation-sensitive-PCR showed an increased methylation of the IFNLR1 promoter and inhibition of DNA methyltransferase activity partially reactivated IFNLR1 expression in HGT-NV and HGT-cured cells indicating that host adaptation occurred via epigenetic reprogramming. Moreover, IFNLR1 ectopic expression rescued response to IFN-λ and restricted HuNoV replication in HGT-NV cells. We conclude that type III IFN is important in inhibiting HuNoV replication in vitro and that the loss of IFNLR1 enhances replication of HuNoV. This study unravels for the first time epigenetic reprogramming of the interferon lambda receptor as a new mechanism of cellular adaptation during long-term RNA virus replication and shows that an endogenous level of interferon lambda signalling is able to control human norovirus replication.
Cambridge Trust Cambridge-Africa PhD studentship
Wellcome Trust (097997/Z/11/Z)
WELLCOME TRUST (097997/Z/11/A)
Wellcome Trust (207498/Z/17/Z)
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External DOI: https://doi.org/10.1128/mBio.02155-19
This record's URL: https://www.repository.cam.ac.uk/handle/1810/296437
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