Viral complementation of immunodeficiency confers protection against enteric pathogens via interferon-λ

Ingle, Harshad; Lee, Sang‐Hyun; Ai, Teresa L.; Orvedahl, Anthony; Rodgers, Rachel; Zhao, Guoyan; Sullender, Meagan E.; Peterson, Stefan T.; Locke, Marissa C.; Liu, Ta‐Chiang; Yokoyama, Christine C.; Sharp, Bridgett; Schultz‐Cherry, Stacey; Miner, Jonathan J.; Baldridge, Megan T.

doi:10.1038/s41564-019-0416-7

Cited by 85 publications

(77 citation statements)

References 47 publications

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“…This response is shared with AstV in other species. For example, murine AstV infection induces IFN-λ in intestinal epithelial cells, which depending on the mouse background, can protect the animals from subsequent murine norovirus or murine rotavirus infection [62]. Interestingly, while this response is shared with influenza virus, a respiratory virus, which also induces both type I and III IFNs in primary lung epithelial cells [63,64], it is different from rotavirus, which upregulated only type III, but not type I IFNs, in HIE [65,66].…”

Section: Fig 8 Pharmacological Blockage Of Endogenous Ifn Response Imentioning

confidence: 99%

Astrovirus replication in human intestinal enteroids reveals multi-cellular tropism and an intricate host innate immune landscape

et al. 2019

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Human astroviruses (HAstV) are understudied positive-strand RNA viruses that cause gastroenteritis mostly in children and the elderly. Three clades of astroviruses, classic, MLBtype and VA-type have been reported in humans. One limitation towards a better understanding of these viruses has been the lack of a physiologically relevant cell culture model that supports growth of all clades of HAstV. Herein, we demonstrate infection of HAstV strains belonging to all three clades in epithelium-only human intestinal enteroids (HIE) isolated from biopsy-derived intestinal crypts. A detailed investigation of infection of VA1, a member of the non-canonical HAstV-VA/HMO clade, showed robust replication in HIE derived from different patients and from different intestinal regions independent of the cellular differentiation status. Flow cytometry and immunofluorescence analysis revealed that VA1 infects several cell types, including intestinal progenitor cells and mature enterocytes, in HIE cultures. RNA profiling of VA1-infected HIE uncovered that the host response to infection is dominated by interferon (IFN)-mediated innate immune responses. A comparison of the antiviral host response in non-transformed HIE and transformed human colon carcinoma Caco-2 cells highlighted significant differences between these cells, including an increased magnitude of the response in HIE. Additional studies confirmed the sensitivity of VA1 to exogenous IFNs, and indicated that the endogenous IFN response of HIE to curtail the growth of strains from all three clades. Genotypic variation in the permissiveness of different HIE lines to HAstV could be overcome by pharmacologic inhibition of JAK/STAT PLOS Pathogens | https://doi.and ALSAC to SSC.; NIH R21 NS101371 to DW; Wellcome Trust: Ref 207498/Z/ signaling. Collectively, our data identify HIE as a universal infection model for HAstV and an improved model of the intestinal epithelium to investigate enteric virus-host interactions. Author summaryHuman astroviruses (HAstV) are understudied positive-strand RNA viruses that typically cause gastroenteritis mostly in children and the elderly, but more recent studies also implicate them in neurological disease in immunocompromised patients. To better understand these viruses, a physiologically relevant cell culture model that supports growth of all clades of HAstV would be highly beneficial. Herein, we demonstrated robust infection of HAstV strains belonging to all three clades in epithelium-only human intestinal enteroids (HIE) isolated from biopsy-derived intestinal crypts from different patients and intestinal regions, making HIE a valuable model to study HAstV biology. Using this system, we identify for the first time that VA1 infects several cell types, including intestinal progenitor cells and mature enterocytes. Analysis of the antiviral host response to infection demonstrated that HIE respond to infection with a type I and III interferon response. This response reduced HAstV replication and when blocked resulted in increased infection. Establis...

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Section: Fig 8 Pharmacological Blockage Of Endogenous Ifn Response Imentioning

confidence: 99%

Astrovirus replication in human intestinal enteroids reveals multi-cellular tropism and an intricate host innate immune landscape

et al. 2019

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“…Enteric bacteria counteract the Type III IFN response, enabling the establishment of persistent infection [29]. Interestingly, the induction of Type III IFN by murine astrovirus can provide protection against MNoV [43], indicating that the interplay between viruses and microbiota extends beyond bacteria.…”

Section: Modulation Of Innate and Adaptive Immune Responses By The MImentioning

confidence: 99%

Virus interactions with bacteria: Partners in the infectious dance

Neu

Mainou

2020

PLoS Pathog

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The outcome of viral infection depends on the interplay between host factors and the environment. Host factors, like the expression of viral receptors, convey permissiveness to infection, define tropism, regulate antiviral immune responses, determine viral clearance, and spread. The host microbiota, the constellation of microbes inhabiting an organism, also plays a key role in the outcome of infection. Microbes and microbial products can directly interact with viral particles. Our understanding of how the microbiota impacts virus infection is largely limited to the bacterial component of the microbiota. Although bacteria do not support eukaryotic virus infection, they can promote viral fitness by enhancing virion stability, promoting infection of eukaryotic cells, and increasing coinfection rates. Virus binding of bacteria can also impact bacterial biology, including bacterial adherence to eukaryotic cells. These interactions can also indirectly affect the host response to viral infection. In this Pearl, we focus on how direct and indirect interactions between viruses and bacteria impact viral biology and touch on recent findings that illustrate how bacterial biology can also be impacted by interactions with eukaryotic viruses (Fig 1).

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“…Figure 367 12). A recent study has shown that production of a type III interferon mediated 368 antiviral immune response in mice was key to protect them from subsequent 369 enteric virus infections (Ingle et al, 2019). This suggests that production of type 370 III IFN against enteric viruses is key to protecting the gut against further 371 challenges.…”

mentioning

confidence: 99%

Cellular polarity asymmetrically functionalizes pathogen recognition receptor-mediated intrinsic immune response in human intestinal epithelium cells

Stanifer

Muenchau

Pervolaraki

et al. 2018

Preprint

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50Intestinal epithelial cells (IECs) act as a physical barrier separating the 51 commensal-containing intestinal tract from the sterile interior. These cells have 52 found a complex balance allowing them to be prepared for pathogen attacks 53 while still tolerating the presence of bacteria/viral stimuli present in the lumen 54 of the gut. Using primary human IECs, we probed the mechanisms, which allow 55 for such a tolerance. We discovered that viral infection emanating from the 56 basolateral side of IECs elicited a stronger intrinsic immune response as 57 compared to lumenal apical infection. We determined that this asymmetric 58 immune response was driven by the clathrin-sorting adapter AP-1B which 59 mediates the polarized sorting of Toll-like receptor 3 (TLR3) toward the 60 basolateral side of IECs. Mice and human IECs lacking AP-1B showed an 61 exacerbated immune response following apical stimulation. Together these 62 results suggest a model where the cellular polarity program plays an integral 63 role in the ability of IECs to partially tolerate apical commensals while remaining 64 fully responsive against invasive basolateral pathogens. 65 66 Keywords: Intrinsic innate immunity, type III interferon, TLR3, cellular polarity, 67 clathrin, AP-1B, lambda interferon, enteric viruses, organoids, intestinal 68 epithelial cells 69 70 71

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Viral complementation of immunodeficiency confers protection against enteric pathogens via interferon-λ

Cited by 85 publications

References 47 publications

Astrovirus replication in human intestinal enteroids reveals multi-cellular tropism and an intricate host innate immune landscape

Astrovirus replication in human intestinal enteroids reveals multi-cellular tropism and an intricate host innate immune landscape

Virus interactions with bacteria: Partners in the infectious dance

Cellular polarity asymmetrically functionalizes pathogen recognition receptor-mediated intrinsic immune response in human intestinal epithelium cells

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