Epigenetic Suppression of Interferon Lambda Receptor Expression Leads to Enhanced Human Norovirus Replication <italic toggle="yes">In Vitro</italic>

ABSTRACT 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 tha...

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Autores principales:	Sabastine E. Arthur, Frédéric Sorgeloos, Myra Hosmillo, Ian G. Goodfellow
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2019
Materias:	DNA methylation human norovirus replicon epigenetic reprogramming interferon lambda receptor microarrays Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/30e4448b669c48de83abfa27f01d9531
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spelling	oai:doaj.org-article:30e4448b669c48de83abfa27f01d95312021-11-15T15:59:41ZEpigenetic Suppression of Interferon Lambda Receptor Expression Leads to Enhanced Human Norovirus Replication <italic toggle="yes">In Vitro</italic>10.1128/mBio.02155-192150-7511https://doaj.org/article/30e4448b669c48de83abfa27f01d95312019-10-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.02155-19https://doaj.org/toc/2150-7511ABSTRACT 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 interferon (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 favoring 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 that 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 signaling is able to control human norovirus replication. IMPORTANCE Noroviruses are one of the most widespread causes of gastroenteritis, yet no suitable therapeutics are available for their control. Moreover, to date, knowledge of the precise cellular processes that control the replication of the human norovirus remains ill defined. Recent work has highlighted the importance of type III interferon (IFN) responses in the restriction of viruses that infect the intestine. Here, we analyzed the adaptive changes required to support long-term replication of noroviruses in cell culture and found that the receptor for type III IFN is decreased in its expression. We confirmed that this decreased expression was driven by epigenetic modifications and that cells lacking the type III IFN receptor are more permissive for norovirus replication. This work provides new insights into key host-virus interactions required for the control of noroviruses and opens potential novel avenues for their therapeutic control.Sabastine E. ArthurFrédéric SorgeloosMyra HosmilloIan G. GoodfellowAmerican Society for MicrobiologyarticleDNA methylationhuman norovirus repliconepigenetic reprogramminginterferon lambda receptormicroarraysMicrobiologyQR1-502ENmBio, Vol 10, Iss 5 (2019)
institution	DOAJ
collection	DOAJ
language	EN
topic	DNA methylation human norovirus replicon epigenetic reprogramming interferon lambda receptor microarrays Microbiology QR1-502
spellingShingle	DNA methylation human norovirus replicon epigenetic reprogramming interferon lambda receptor microarrays Microbiology QR1-502 Sabastine E. Arthur Frédéric Sorgeloos Myra Hosmillo Ian G. Goodfellow Epigenetic Suppression of Interferon Lambda Receptor Expression Leads to Enhanced Human Norovirus Replication <italic toggle="yes">In Vitro</italic>
description	ABSTRACT 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 interferon (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 favoring 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 that 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 signaling is able to control human norovirus replication. IMPORTANCE Noroviruses are one of the most widespread causes of gastroenteritis, yet no suitable therapeutics are available for their control. Moreover, to date, knowledge of the precise cellular processes that control the replication of the human norovirus remains ill defined. Recent work has highlighted the importance of type III interferon (IFN) responses in the restriction of viruses that infect the intestine. Here, we analyzed the adaptive changes required to support long-term replication of noroviruses in cell culture and found that the receptor for type III IFN is decreased in its expression. We confirmed that this decreased expression was driven by epigenetic modifications and that cells lacking the type III IFN receptor are more permissive for norovirus replication. This work provides new insights into key host-virus interactions required for the control of noroviruses and opens potential novel avenues for their therapeutic control.
format	article
author	Sabastine E. Arthur Frédéric Sorgeloos Myra Hosmillo Ian G. Goodfellow
author_facet	Sabastine E. Arthur Frédéric Sorgeloos Myra Hosmillo Ian G. Goodfellow
author_sort	Sabastine E. Arthur
title	Epigenetic Suppression of Interferon Lambda Receptor Expression Leads to Enhanced Human Norovirus Replication <italic toggle="yes">In Vitro</italic>
title_short	Epigenetic Suppression of Interferon Lambda Receptor Expression Leads to Enhanced Human Norovirus Replication <italic toggle="yes">In Vitro</italic>
title_full	Epigenetic Suppression of Interferon Lambda Receptor Expression Leads to Enhanced Human Norovirus Replication <italic toggle="yes">In Vitro</italic>
title_fullStr	Epigenetic Suppression of Interferon Lambda Receptor Expression Leads to Enhanced Human Norovirus Replication <italic toggle="yes">In Vitro</italic>
title_full_unstemmed	Epigenetic Suppression of Interferon Lambda Receptor Expression Leads to Enhanced Human Norovirus Replication <italic toggle="yes">In Vitro</italic>
title_sort	epigenetic suppression of interferon lambda receptor expression leads to enhanced human norovirus replication <italic toggle="yes">in vitro</italic>
publisher	American Society for Microbiology
publishDate	2019
url	https://doaj.org/article/30e4448b669c48de83abfa27f01d9531
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Epigenetic Suppression of Interferon Lambda Receptor Expression Leads to Enhanced Human Norovirus Replication <italic toggle="yes">In Vitro</italic>

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