Norovirus Replication in Human Intestinal Epithelial Cells Is Restricted by the Interferon-Induced JAK/STAT Signaling Pathway and RNA Polymerase II-Mediated Transcriptional Responses

ABSTRACT Human noroviruses (HuNoV) are a leading cause of viral gastroenteritis worldwide and a significant cause of morbidity and mortality in all age groups. The recent finding that HuNoV can be propagated in B cells and mucosa-derived intestinal epithelial organoids (IEOs) has transformed our abi...

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Autores principales:	Myra Hosmillo, Yasmin Chaudhry, Komal Nayak, Frederic Sorgeloos, Bon-Kyoung Koo, Alessandra Merenda, Reidun Lillestol, Lydia Drumright, Matthias Zilbauer, Ian Goodfellow
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2020
Materias:	intestine organoid interferons mucosal pathogens noroviruses Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/e094082be0f14373847279071b1750d4
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spelling	oai:doaj.org-article:e094082be0f14373847279071b1750d42021-11-15T15:57:02ZNorovirus Replication in Human Intestinal Epithelial Cells Is Restricted by the Interferon-Induced JAK/STAT Signaling Pathway and RNA Polymerase II-Mediated Transcriptional Responses10.1128/mBio.00215-202150-7511https://doaj.org/article/e094082be0f14373847279071b1750d42020-04-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.00215-20https://doaj.org/toc/2150-7511ABSTRACT Human noroviruses (HuNoV) are a leading cause of viral gastroenteritis worldwide and a significant cause of morbidity and mortality in all age groups. The recent finding that HuNoV can be propagated in B cells and mucosa-derived intestinal epithelial organoids (IEOs) has transformed our ability to dissect the life cycle of noroviruses. Using transcriptome sequencing (RNA-Seq) of HuNoV-infected intestinal epithelial cells (IECs), we have found that replication of HuNoV in IECs results in interferon (IFN)-induced transcriptional responses and that HuNoV replication in IECs is sensitive to IFN. This contrasts with previous studies that suggested that the innate immune response may play no role in the restriction of HuNoV replication in immortalized cells. We demonstrated that inhibition of Janus kinase 1 (JAK1)/JAK2 enhanced HuNoV replication in IECs. Surprisingly, targeted inhibition of cellular RNA polymerase II-mediated transcription was not detrimental to HuNoV replication but instead enhanced replication to a greater degree than blocking of JAK signaling directly. Furthermore, we demonstrated for the first time that IECs generated from genetically modified intestinal organoids, engineered to be deficient in the interferon response, were more permissive to HuNoV infection. Taking the results together, our work revealed that IFN-induced transcriptional responses restrict HuNoV replication in IECs and demonstrated that inhibition of these responses mediated by modifications of the culture conditions can greatly enhance the robustness of the norovirus culture system. IMPORTANCE Noroviruses are a major cause of gastroenteritis worldwide, and yet the challenges associated with their growth in culture have greatly hampered the development of therapeutic approaches and have limited our understanding of the cellular pathways that control infection. Here, we show that human intestinal epithelial cells, which represent the first point of entry of human noroviruses into the host, limit virus replication by induction of innate responses. Furthermore, we show that modulating the ability of intestinal epithelial cells to induce transcriptional responses to HuNoV infection can significantly enhance human norovirus replication in culture. Collectively, our findings provide new insights into the biological pathways that control norovirus infection but also identify mechanisms that enhance the robustness of norovirus culture.Myra HosmilloYasmin ChaudhryKomal NayakFrederic SorgeloosBon-Kyoung KooAlessandra MerendaReidun LillestolLydia DrumrightMatthias ZilbauerIan GoodfellowAmerican Society for Microbiologyarticleintestineorganoidinterferonsmucosal pathogensnorovirusesMicrobiologyQR1-502ENmBio, Vol 11, Iss 2 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	intestine organoid interferons mucosal pathogens noroviruses Microbiology QR1-502
spellingShingle	intestine organoid interferons mucosal pathogens noroviruses Microbiology QR1-502 Myra Hosmillo Yasmin Chaudhry Komal Nayak Frederic Sorgeloos Bon-Kyoung Koo Alessandra Merenda Reidun Lillestol Lydia Drumright Matthias Zilbauer Ian Goodfellow Norovirus Replication in Human Intestinal Epithelial Cells Is Restricted by the Interferon-Induced JAK/STAT Signaling Pathway and RNA Polymerase II-Mediated Transcriptional Responses
description	ABSTRACT Human noroviruses (HuNoV) are a leading cause of viral gastroenteritis worldwide and a significant cause of morbidity and mortality in all age groups. The recent finding that HuNoV can be propagated in B cells and mucosa-derived intestinal epithelial organoids (IEOs) has transformed our ability to dissect the life cycle of noroviruses. Using transcriptome sequencing (RNA-Seq) of HuNoV-infected intestinal epithelial cells (IECs), we have found that replication of HuNoV in IECs results in interferon (IFN)-induced transcriptional responses and that HuNoV replication in IECs is sensitive to IFN. This contrasts with previous studies that suggested that the innate immune response may play no role in the restriction of HuNoV replication in immortalized cells. We demonstrated that inhibition of Janus kinase 1 (JAK1)/JAK2 enhanced HuNoV replication in IECs. Surprisingly, targeted inhibition of cellular RNA polymerase II-mediated transcription was not detrimental to HuNoV replication but instead enhanced replication to a greater degree than blocking of JAK signaling directly. Furthermore, we demonstrated for the first time that IECs generated from genetically modified intestinal organoids, engineered to be deficient in the interferon response, were more permissive to HuNoV infection. Taking the results together, our work revealed that IFN-induced transcriptional responses restrict HuNoV replication in IECs and demonstrated that inhibition of these responses mediated by modifications of the culture conditions can greatly enhance the robustness of the norovirus culture system. IMPORTANCE Noroviruses are a major cause of gastroenteritis worldwide, and yet the challenges associated with their growth in culture have greatly hampered the development of therapeutic approaches and have limited our understanding of the cellular pathways that control infection. Here, we show that human intestinal epithelial cells, which represent the first point of entry of human noroviruses into the host, limit virus replication by induction of innate responses. Furthermore, we show that modulating the ability of intestinal epithelial cells to induce transcriptional responses to HuNoV infection can significantly enhance human norovirus replication in culture. Collectively, our findings provide new insights into the biological pathways that control norovirus infection but also identify mechanisms that enhance the robustness of norovirus culture.
format	article
author	Myra Hosmillo Yasmin Chaudhry Komal Nayak Frederic Sorgeloos Bon-Kyoung Koo Alessandra Merenda Reidun Lillestol Lydia Drumright Matthias Zilbauer Ian Goodfellow
author_facet	Myra Hosmillo Yasmin Chaudhry Komal Nayak Frederic Sorgeloos Bon-Kyoung Koo Alessandra Merenda Reidun Lillestol Lydia Drumright Matthias Zilbauer Ian Goodfellow
author_sort	Myra Hosmillo
title	Norovirus Replication in Human Intestinal Epithelial Cells Is Restricted by the Interferon-Induced JAK/STAT Signaling Pathway and RNA Polymerase II-Mediated Transcriptional Responses
title_short	Norovirus Replication in Human Intestinal Epithelial Cells Is Restricted by the Interferon-Induced JAK/STAT Signaling Pathway and RNA Polymerase II-Mediated Transcriptional Responses
title_full	Norovirus Replication in Human Intestinal Epithelial Cells Is Restricted by the Interferon-Induced JAK/STAT Signaling Pathway and RNA Polymerase II-Mediated Transcriptional Responses
title_fullStr	Norovirus Replication in Human Intestinal Epithelial Cells Is Restricted by the Interferon-Induced JAK/STAT Signaling Pathway and RNA Polymerase II-Mediated Transcriptional Responses
title_full_unstemmed	Norovirus Replication in Human Intestinal Epithelial Cells Is Restricted by the Interferon-Induced JAK/STAT Signaling Pathway and RNA Polymerase II-Mediated Transcriptional Responses
title_sort	norovirus replication in human intestinal epithelial cells is restricted by the interferon-induced jak/stat signaling pathway and rna polymerase ii-mediated transcriptional responses
publisher	American Society for Microbiology
publishDate	2020
url	https://doaj.org/article/e094082be0f14373847279071b1750d4
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Norovirus Replication in Human Intestinal Epithelial Cells Is Restricted by the Interferon-Induced JAK/STAT Signaling Pathway and RNA Polymerase II-Mediated Transcriptional Responses

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