Interferon-λ and interleukin 22 act synergistically for the induction of interferon-stimulated genes and control of rotavirus infection

Hernández, Pedro P.; Mahlakõiv, Tanel; Yang, Ines; Schwierzeck, Vera; Nguyen, Nam Trung; Guendel, Fabian; Gronke, Konrad; Ryffel, Bernhard; Hölscher, Christoph; Dumoutier, Laure; Renauld, Jean‐Christophe; Suerbaum, Sebastian; Staeheli, Peter; Diefenbach, Andreas

doi:10.1038/ni.3180

Cited by 264 publications

(287 citation statements)

References 68 publications

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“…The protective effects of IFN-λ in acute rotavirus infection in mice are enhanced by IL-22, which also cured chronic murine rotavirus infection (54,61). In the HIE model, pretreatment with IL-22 decreased HRV replication by 54% (Fig.…”

Section: Exogenous Ifn Treatment Restricts Rotavirus Growth In Hiesmentioning

confidence: 89%

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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.

114

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: Exogenous Ifn Treatment Restricts Rotavirus Growth In Hiesmentioning

confidence: 89%

“…4). However, endogenous type III IFN restricts animal rotavirus replication in mice (54,55). The mouse epithelium was thought to produce the type III IFN in vivo, although immune cells can also produce type III IFN (54,56,57).…”

Section: Exogenous Ifn Treatment Restricts Rotavirus Growth In Hiesmentioning

confidence: 99%

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.

114

150

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“…Nonetheless, NKp46 + ILC3 may have other important non‐redundant roles during C. rodentium infection, as infected mice lacking NKp46 + ILC3 exhibited severe caecal damage 84. In addition, intestinal ILC3‐derived IL‐22 may also contribute to immunity roles in a diverse range of clinically relevant infections in the gut including the nosocomial pathogen Clostridium difficile ,119 rotavirus,120 the fungal pathogen Candida albicans ,121 as well as gastrointestinal helminths 78. In contrast, some enteric pathogens have evolved to circumvent and exploit the ILC3 response to infection.…”

Section: Ilc3 In Inflammation and Infectionmentioning

confidence: 99%

Functional and phenotypic heterogeneity of group 3 innate lymphoid cells

2017

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SummaryGroup 3 innate lymphoid cells (ILC3), defined by expression of the transcription factor retinoid‐related orphan receptor γt, play key roles in the regulation of inflammation and immunity in the gastrointestinal tract and associated lymphoid tissues. ILC3 consist largely of two major subsets, NCR + ILC3 and LTi‐like ILC3, but also demonstrate significant plasticity and heterogeneity. Recent advances have begun to dissect the relationship between ILC3 subsets and to define distinct functional states within the intestinal tissue microenvironment. In this review we discuss the ever‐expanding roles of ILC3 in the context of intestinal homeostasis, infection and inflammation – with a focus on comparing and contrasting the relative contributions of ILC3 subsets.

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“…148 Whereas ILC1s and ILC3s are essential to host defense against infection by viruses, intracellular bacteria and parasites, ILC2s potently drive type 2 inflammation and mediate allergic inflammation, tissue repair and anti-helminth innate immunity. [149][150][151][152][153] A novel population of IL-25-responsive inflammatory ILC2 (iILC2) could develop into IL-33-responsive natural ILC2 (nILC2)-like cells and contribute to immunity to both helminths and fungi. 154,155 Inflammatory cytokines such as IL-1 and IFN, 156,157 and crosstalk with stromal cells, epithelial cells and various immune cells such as DC, 158 T cells 159 and B cells 160,161 are important for regulation of ILC function and plasticity at the crossroad of homeostasis and inflammation.…”

Section: Innate Lymphoid Cellsmentioning

confidence: 99%