Norovirus replication in human intestinal epithelial cells is restricted by the interferon-induced JAK/STAT signalling pathway and RNA Polymerase II mediated transcriptional responses

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 capability...

Full description

Saved in:
Bibliographic Details
Published inbioRxiv
Main Authors Hosmillo, Myra T, Chaudhry, Yasmin, Nayak, Komal, Sorgeloos, Frederic, Koo, Bon-Kyoung, Merenda, Alessandra, Lillestol, Reidun, Drumright, Lydia, Zilbauer, Matthias, Goodfellow, Ian G
Format Paper
LanguageEnglish
Published Cold Spring Harbor Cold Spring Harbor Laboratory Press 10.08.2019
Subjects
Cell culture
DNA-directed RNA polymerase
Epithelial cells
Gastroenteritis
Innate immunity
Interferon
Intestine
Janus kinase
Janus kinase 2
Life cycles
Lymphocytes B
Morbidity
Mucosa
Organoids
Replication
RNA polymerase
Signal transduction
Transcription
Online AccessGet full text

Cover

More Information
Summary: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 capability to dissect the life cycle of noroviruses. Using RNA-Seq of HuNoV infected intestinal epithelial cells (IECs), we have found that replication of HuNoV in IECs results in interferon-induced transcriptional responses and that HuNoV replication in IECs is sensitive to IFN. This contrasts with previous studies that suggest that the innate immune response may play no role in the restriction of HuNoV replication in immortalised cells. We demonstrate that the inhibition of JAK1/JAK2 enhances HuNoV replication in IECs. Surprisingly, targeted inhibition of cellular RNA polymerase II-mediated transcription was not detrimental to HuNoV replication, but enhanced replication to a greater degree compared to blocking of JAK signalling directly. Furthermore, we demonstrate for the first time that IECs generated from genetically modified intestinal organoids, engineered to be deficient in the interferon response, are more permissive to HuNoV infection. Together our work identifies the IFN-induced transcriptional responses restrict HuNoV replication in IECs and demonstrates that the inhibition of these responses by modifications to the culture conditions can greatly enhance the robustness of the norovirus culture system.
DOI:10.1101/731802