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bioRxiv · 10.1101/523282

Epigenetic suppression of interferon lambda receptor expression leads to an enhanced HuNoV replication in vitro

Arthur, S. E.·Sorgeloos, F.·Hosmillo, M.·Goodfellow, I.
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Abstract

Human norovirus (HuNoV) is the main cause of acute gastroenteritis worldwide yet no therapeutics are currently available. Here, we utilize a human norovirus replicon in epithelial 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 the replication of viral RNA. Microarray analysis was used to identify genes differentially regulated in HGT-NV and HGT-cured compared to parental HGT cells. We found that the IFN lambda receptor alpha (IFNLR1) expression was highly reduced in HGT-NV and HGT-cured cells. All three cell lines responded to exogenous IFN-{beta} by inducing interferon stimulated genes (ISGs), however, HGT-NV and HGT-cured failed to respond to exogenous IFN-{lambda}. Inhibition of DNA methyltransferase activity with 5-aza-2-deoxycytidine partially reactivated IFNLR1 expression in HGT-NV and IFN-cured cells suggesting that host adaptation occurred via epigenetic reprogramming. In line with this observation, ectopic expression of the IFN-{lambda} receptor alpha rescued HGT-NV and HGT-cured cells response to IFN-{lambda}. We conclude that type III IFN is important in inhibiting HuNoV replication in vitro and that the loss of IFNLR1 enhances replication of HuNoV. To the best of our knowledge, this study unravels for the first time epigenetic reprograming 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.

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Arthur, S. E., Sorgeloos, F., Hosmillo, M., Goodfellow, I.. 2019-01-17. Epigenetic suppression of interferon lambda receptor expression leads to an enhanced HuNoV replication in vitro. https://doi.org/10.1101/523282

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