Modeling rotavirus infection and antiviral therapy using primary intestinal organoids

Yin, Yuebang; Bijvelds, Marcel J. C.; Wen, Dandan; Xu, Lei; Eijk, Annemiek A. van der; Knipping, Karen; Tüysüz, Nesrin; Dekkers, Johanna F.; Wang, Yijin; Jonge, Jeroen de; Sprengers, Dave; Laan, Luc J. W. van der; Beekman, Jeffrey M.; Berge, Derk ten; Metselaar, Herold J.; Jonge, Hugo de; Koopmans, Marion; Peppelenbosch, Maikel P.

doi:10.1016/j.antiviral.2015.09.010

Cited by 158 publications

(178 citation statements)

References 33 publications

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“…This differs from reports in mice, in which exogenous treatment with IFN-λ is more protective against enteric viral replication than type I IFN (55,56), and type I IFN is primarily considered to inhibit systemic spread of enteric viruses (17,56,75). This difference may be a result of the type I IFN subtype tested; previous studies in mice and HIEs used an IFN-α subtype rather than IFN-β for exogenous treatment (17,55,56,83); however, IFN-α2 was significantly weaker than IFN-β in restricting HRV growth in HIEs. Heterogeneity in the host response to different type I IFNs has been previously characterized; IFN-β binds the type I IFN receptor with greater affinity than IFN-α2 (84), and other viral pathogens including LCMV and HCV have differing sensitivities to IFN-α and IFN-β (60).…”

Section: Discussionmentioning

confidence: 60%

A paradox of transcriptional and functional innate interferon responses of human intestinal enteroids to enteric virus infection

Saxena

Simon

Zeng

et al. 2017

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

112

150

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The intestinal epithelium can limit enteric pathogens by producing antiviral cytokines, such as IFNs. Type I IFN (IFN-α/β) and type III IFN (IFN-λ) function at the epithelial level, and their respective efficacies depend on the specific pathogen and site of infection. However, the roles of type I and type III IFN in restricting human enteric viruses are poorly characterized as a result of the difficulties in cultivating these viruses in vitro and directly obtaining control and infected small intestinal human tissue. We infected nontransformed human intestinal enteroid cultures from multiple individuals with human rotavirus (HRV) and assessed the host epithelial response by using RNAsequencing and functional assays. The dominant transcriptional pathway induced by HRV infection is a type III IFN-regulated response. Early after HRV infection, low levels of type III IFN protein activate IFN-stimulated genes. However, this endogenous response does not restrict HRV replication because replication-competent HRV antagonizes the type III IFN response at pre-and posttranscriptional levels. In contrast, exogenous IFN treatment restricts HRV replication, with type I IFN being more potent than type III IFN, suggesting that extraepithelial sources of type I IFN may be the critical IFN for limiting enteric virus replication in the human intestine.enteric virus | interferon | human enteroids | human rotavirus T he human small intestinal epithelium is the primary site of infection and replication for many gastrointestinal pathogens. However, fundamental knowledge about intestinal epithelial cellpathogen interactions in humans is limited as a result of the impracticality of studying these cells in vivo. Modeling these interactions in vitro is difficult because many human enteric pathogens fail to replicate or replicate poorly in cancer cell lines derived primarily from the human colon (1-4). Human intestinal enteroids (HIEs) represent a new in vitro model of the human small intestinal epithelium; this model was developed following advances in stem cell biology, and it recapitulates many of the biological and physiological properties of the human small intestine in vivo (5, 6). Unlike other in vitro models, HIEs are easily established from nontransformed small intestinal tissue, can be maintained on a long-term basis, and contain a stem cell niche and the diversity of intestinal epithelial cell types (enterocytes, goblet, enteroendocrine, and Paneth cells) present in vivo (6, 7). HIEs allow for comparisons of intestinal host responses across genetically diverse individuals (8) and reproduce many of the in vivo pathophysiological properties of infection by a human enteric viral pathogen, human rotavirus (HRV) (9).HRVs are the major etiology of severe diarrhea in children under the age of 5 y worldwide, resulting in an estimated 215,000 deaths annually (10). HRVs replicate to high titers in humans but replicate poorly or not at all in small animal models (11,12). This host restriction of HRV in animal models is based on properties o...

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Section: Discussionmentioning

confidence: 60%

A paradox of transcriptional and functional innate interferon responses of human intestinal enteroids to enteric virus infection

Saxena

Simon

Zeng

et al. 2017

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

112

150

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“…Both human proximal small intestinal enteroids and HIOs have been shown to model human rotavirus infection 39,60,81,82 . Rotavirus replicates and produces infectious virions in enteroids and HIOs, with viral replication increasing over 96 h 60,82 .…”

Section: Host–pathogen Interactionsmentioning

confidence: 99%

“…Rotavirus replicates and produces infectious virions in enteroids and HIOs, with viral replication increasing over 96 h 60,82 . Moreover, an increased degree of infection (~50%) in differentiated human enteroids exposed to human rotavirus has been demonstrated compared to simian strains 60 .…”

Section: Host–pathogen Interactionsmentioning

confidence: 99%

Human mini-guts: new insights into intestinal physiology and host–pathogen interactions

In¹,

Foulke‐Abel²,

Estes³

et al. 2016

Nat Rev Gastroenterol Hepatol

105

118

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The development of indefinitely propagating human ‘mini-guts’ has led to a rapid advance in gastrointestinal research related to transport physiology, developmental biology, pharmacology, and pathophysiology. These mini-guts, also called enteroids or colonoids, are derived from LGR5+ intestinal stem cells isolated from the small intestine or colon. Addition of WNT3A and other growth factors promotes stemness and results in viable, physiologically functional human intestinal or colonic cultures that develop a crypt–villus axis and can be differentiated into all intestinal epithelial cell types. The success of research using human enteroids has highlighted the limitations of using animals or in vitro, cancer-derived cell lines to model transport physiology and pathophysiology. For example, curative or preventive therapies for acute enteric infections have been limited, mostly due to the lack of a physiological human intestinal model. However, the human enteroid model enables specific functional studies of secretion and absorption in each intestinal segment as well as observations of the earliest molecular events that occur during enteric infections. This Review describes studies characterizing these human mini-guts as a physiological model to investigate intestinal transport and host pathogen interactions.

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“…Rotaviruses not only efficiently replicated in the organoids, but infected organoids also produced infectious virus particles. Viral replication could be blocked by treatment of the infected organoids with the antiviral agents interferon-α or ribavirin (Yin et al, 2015). Another striking example of organoid-virus co-culture is the use of induced pluripotent stem cell (iPSC)-derived brain organoids to investigate the effects of Zika virus (ZIKV) infection on brain development (Qian et al, 2017).…”

Section: Host-pathogen Interactionsmentioning

confidence: 99%

Translational applications of adult stem cell-derived organoids

2017

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Adult stem cells from a variety of organs can be expanded longterm in vitro as three-dimensional organotypic structures termed organoids. These adult stem cell-derived organoids retain their organ identity and remain genetically stable over long periods of time. The ability to grow organoids from patient-derived healthy and diseased tissue allows for the study of organ development, tissue homeostasis and disease. In this Review, we discuss the generation of adult stem cell-derived organoid cultures and their applications in in vitro disease modeling, personalized cancer therapy and regenerative medicine.

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Modeling rotavirus infection and antiviral therapy using primary intestinal organoids

Cited by 158 publications

References 33 publications

A paradox of transcriptional and functional innate interferon responses of human intestinal enteroids to enteric virus infection

A paradox of transcriptional and functional innate interferon responses of human intestinal enteroids to enteric virus infection

Human mini-guts: new insights into intestinal physiology and host–pathogen interactions

Translational applications of adult stem cell-derived organoids

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