Type III interferon signaling restricts enterovirus 71 infection of goblet cells

Good, Charles A.; Wells, Alexandra I.; Coyne, Carolyn B.

doi:10.1126/sciadv.aau4255

Cited by 91 publications

(97 citation statements)

References 40 publications

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“…Once internalized, it is possible that the interaction between FcRn and echoviruses is altered by the low pH of endosomes, which may facilitate subsequent genome release and/or endosomal escape. We have shown that E11 preferentially infects enterocytes (10), with enhanced infection from the basolateral surface of human intestinal epithelial (HIE) cells (29). This polarity of infection is consistent with the enhanced expression of FcRn in enterocytes in the intestine and its enrichment to the basolateral surface.…”

Section: Discussionsupporting

confidence: 70%

“…This polarity of infection is consistent with the enhanced expression of FcRn in enterocytes in the intestine and its enrichment to the basolateral surface. Following replication, E11 is released bidirectionally from HIE from both the apical and basolateral domains (29). Given that FcRn mediates bidirectional transport (30), this raises the possibility that echoviruses could be transported from either the apical or basolateral domains to cross the intestinal barrier.…”

Section: Discussionmentioning

confidence: 99%

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The neonatal Fc receptor is a pan-echovirus receptor

Morosky

Wells

Lemon

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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Echoviruses are amongst the most common causative agents of aseptic meningitis worldwide and are particularly devastating in the neonatal population, where they are associated with severe hepatitis, neurological disease, including meningitis and encephalitis, and even death. Here, we identify the neonatal Fc receptor (FcRn) as a pan-echovirus receptor. We show that loss of expression of FcRn or its binding partner beta 2 microglobulin (β2M) renders cells resistant to infection by a panel of echoviruses at the stage of virus attachment, and that a blocking antibody to β2M inhibits echovirus infection in cell lines and in primary human intestinal epithelial cells. We also show that expression of human, but not mouse, FcRn renders nonpermissive human and mouse cells sensitive to echovirus infection and that the extracellular domain of human FcRn directly binds echovirus particles and neutralizes infection. Lastly, we show that neonatal mice expressing human FcRn are more susceptible to echovirus infection by the enteral route. Our findings thus identify FcRn as a pan-echovirus receptor, which may explain the enhanced susceptibility of neonates to echovirus infections.

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Section: Discussionsupporting

confidence: 70%

Section: Discussionmentioning

confidence: 99%

The neonatal Fc receptor is a pan-echovirus receptor

Morosky

Wells

Lemon

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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“…The use of pharmacological inhibitors for the stimulation of viral infection has been described in many studies of immortalized cell lines (39,47,80) and more recently for viral infection of intestinal organoids (81). The mechanism of action of Rux is well defined, as it specifically targets the JAK kinases (36).…”

Section: Discussionmentioning

confidence: 99%

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

Hosmillo

Chaudhry

Nayak

et al. 2020

mBio

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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.

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“…For example, only 2 of 12 WT animals and 2 of 13 hFcRn Tg32 animals had any detectable virus in liver and 0 of 12 WT mice and 1 of 13 hFcRn Tg32 mice had detectable virus in the brain, although in both cases, viral titers were very low ( Figure 1B, 1F). Because many enteroviruses are restricted by type I IFN signaling in small animal models and because we have previously shown that E11 is sensitive to recombinant IFN-b treatment 24 , we reasoned that type I IFNs might play a key role in restricting E11 infection in vivo. To test this, we infected suckling mice deficient in type I IFN signaling (IFNAR -/-) with 10 4 PFU E11 by the IP route.…”

Section: Human Fcrn and Type I Ifn Signaling Are Key Host Determinantmentioning

confidence: 99%

Human FcRn expression and Type I Interferon signaling control Echovirus 11 pathogenesis in mice

Wells

Grimes

Kim

et al. 2020

Preprint

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Neonatal echovirus infections are characterized by severe hepatitis and neurological complications that can be fatal. Here, we show that expression of the human homologue of the neonatal Fc receptor (hFcRn), the primary receptor for echoviruses, and ablation of type I interferon (IFN) signaling are key host determinants involved in echovirus pathogenesis. We show that expression of hFcRn alone is insufficient to confer susceptibility to echovirus infections in mice. However, expression of hFcRn in mice deficient in type I interferon (IFN) signaling, hFcRn-IFNAR−/−, recapitulate the echovirus pathogenesis observed in humans. Luminex-based multianalyte profiling from E11 infected hFcRn-IFNAR−/− mice revealed a robust systemic immune response to infection, including the induction of type I IFNs. Furthermore, similar to the severe hepatitis observed in humans, E11 infection in hFcRn-IFNAR−/− mice caused profound liver damage. Our findings define the host factors involved in echovirus pathogenesis and establish in vivo models that recapitulate echovirus disease.

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Type III interferon signaling restricts enterovirus 71 infection of goblet cells

Cited by 91 publications

References 40 publications

The neonatal Fc receptor is a pan-echovirus receptor

The neonatal Fc receptor is a pan-echovirus receptor

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

Human FcRn expression and Type I Interferon signaling control Echovirus 11 pathogenesis in mice

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