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      Astrovirus infects actively secreting goblet cells and alters the gut mucus barrier

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          Abstract

          Astroviruses are a global cause of pediatric diarrhea, but they are largely understudied, and it is unclear how and where they replicate in the gut. Using an in vivo model, here we report that murine astrovirus preferentially infects actively secreting small intestinal goblet cells, specialized epithelial cells that maintain the mucus barrier. Consequently, virus infection alters mucus production, leading to an increase in mucus-associated bacteria and resistance to enteropathogenic E. coli colonization. These studies establish the main target cell type and region of the gut for productive murine astrovirus infection. They further define a mechanism by which an enteric virus can regulate the mucus barrier, induce functional changes to commensal microbial communities, and alter host susceptibility to pathogenic bacteria.

          Abstract

          Astroviruses are the leading cause of pediatric diarrhea, but which cells are the main targets in the gut remains unclear. Here, using an in vivo model of murine astrovirus, the authors show that the virus infects goblet cells and that this alters mucus production and increases mucus-associated bacterial communities in the gut.

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          Most cited references34

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          Recognition of commensal microflora by toll-like receptors is required for intestinal homeostasis.

          Toll-like receptors (TLRs) play a crucial role in host defense against microbial infection. The microbial ligands recognized by TLRs are not unique to pathogens, however, and are produced by both pathogenic and commensal microorganisms. It is thought that an inflammatory response to commensal bacteria is avoided due to sequestration of microflora by surface epithelia. Here, we show that commensal bacteria are recognized by TLRs under normal steady-state conditions, and this interaction plays a crucial role in the maintenance of intestinal epithelial homeostasis. Furthermore, we find that activation of TLRs by commensal microflora is critical for the protection against gut injury and associated mortality. These findings reveal a novel function of TLRs-control of intestinal epithelial homeostasis and protection from injury-and provide a new perspective on the evolution of host-microbial interactions.
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            The mucus and mucins of the goblet cells and enterocytes provide the first defense line of the gastrointestinal tract and interact with the immune system.

            The gastrointestinal tract is covered by mucus that has different properties in the stomach, small intestine, and colon. The large highly glycosylated gel-forming mucins MUC2 and MUC5AC are the major components of the mucus in the intestine and stomach, respectively. In the small intestine, mucus limits the number of bacteria that can reach the epithelium and the Peyer's patches. In the large intestine, the inner mucus layer separates the commensal bacteria from the host epithelium. The outer colonic mucus layer is the natural habitat for the commensal bacteria. The intestinal goblet cells secrete not only the MUC2 mucin but also a number of typical mucus components: CLCA1, FCGBP, AGR2, ZG16, and TFF3. The goblet cells have recently been shown to have a novel gate-keeping role for the presentation of oral antigens to the immune system. Goblet cells deliver small intestinal luminal material to the lamina propria dendritic cells of the tolerogenic CD103(+) type. In addition to the gel-forming mucins, the transmembrane mucins MUC3, MUC12, and MUC17 form the enterocyte glycocalyx that can reach about a micrometer out from the brush border. The MUC17 mucin can shuttle from a surface to an intracellular vesicle localization, suggesting that enterocytes might control and report epithelial microbial challenge. There is communication not only from the epithelial cells to the immune system but also in the opposite direction. One example of this is IL10 that can affect and improve the properties of the inner colonic mucus layer. The mucus and epithelial cells of the gastrointestinal tract are the primary gate keepers and controllers of bacterial interactions with the host immune system, but our understanding of this relationship is still in its infancy. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
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              New developments in goblet cell mucus secretion and function.

              Goblet cells and their main secretory product, mucus, have long been poorly appreciated; however, recent discoveries have changed this and placed these cells at the center stage of our understanding of mucosal biology and the immunology of the intestinal tract. The mucus system differs substantially between the small and large intestine, although it is built around MUC2 mucin polymers in both cases. Furthermore, that goblet cells and the regulation of their secretion also differ between these two parts of the intestine is of fundamental importance for a better understanding of mucosal immunology. There are several types of goblet cell that can be delineated based on their location and function. The surface colonic goblet cells secrete continuously to maintain the inner mucus layer, whereas goblet cells of the colonic and small intestinal crypts secrete upon stimulation, for example, after endocytosis or in response to acetyl choline. However, despite much progress in recent years, our understanding of goblet cell function and regulation is still in its infancy.
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                Author and article information

                Contributors
                stacey.schultz-cherry@stjude.org
                Journal
                Nat Commun
                Nat Commun
                Nature Communications
                Nature Publishing Group UK (London )
                2041-1723
                29 April 2020
                29 April 2020
                2020
                : 11
                : 2097
                Affiliations
                [1 ]ISNI 0000 0001 0224 711X, GRID grid.240871.8, Department of Infectious Diseases, , St. Jude Children’s Research Hospital, ; Memphis, TN USA
                [2 ]ISNI 0000 0001 0224 711X, GRID grid.240871.8, Department of Immunology, , St. Jude Children’s Research Hospital, ; Memphis, TN USA
                [3 ]ISNI 0000 0001 0224 711X, GRID grid.240871.8, Cell and Tissue Imaging Center, , St. Jude Children’s Research Hospital, ; Memphis, TN USA
                [4 ]ISNI 0000 0001 0224 711X, GRID grid.240871.8, Veterinary Pathology Core, , St. Jude Children’s Research Hospital, ; Memphis, TN USA
                Author information
                http://orcid.org/0000-0002-1267-5596
                http://orcid.org/0000-0003-4096-6048
                http://orcid.org/0000-0002-2496-9620
                http://orcid.org/0000-0002-7277-692X
                http://orcid.org/0000-0002-7535-0545
                http://orcid.org/0000-0002-1798-1760
                http://orcid.org/0000-0001-7955-0256
                http://orcid.org/0000-0002-2021-727X
                Article
                15999
                10.1038/s41467-020-15999-y
                7190700
                32350281
                e1eae9bd-7a64-48cc-92e9-e791688b3d73
                © The Author(s) 2020

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 24 October 2019
                : 8 April 2020
                Funding
                Funded by: FundRef https://doi.org/10.13039/100000060, U.S. Department of Health & Human Services | NIH | National Institute of Allergy and Infectious Diseases (NIAID);
                Award ID: T32 AI106700-03
                Award ID: R01 AI121832
                Award ID: R01 AI136514
                Award ID: R21 AI135254-01
                Award ID: R03 AI126101-01
                Award Recipient :
                Funded by: U.S. Department of Health & Human Services | NIH | National Institute of Allergy and Infectious Diseases (NIAID)
                Funded by: U.S. Department of Health & Human Services | NIH | National Institute of Allergy and Infectious Diseases (NIAID)
                Funded by: FundRef https://doi.org/10.13039/100012524, American Lebanese Syrian Associated Charities (ALSAC);
                Funded by: U.S. Department of Health & Human Services | NIH | National Institute of Allergy and Infectious Diseases (NIAID)
                Funded by: U.S. Department of Health & Human Services | NIH | National Institute of Allergy and Infectious Diseases (NIAID)
                Funded by: FundRef https://doi.org/10.13039/100000054, U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI);
                Award ID: P30 CA021765
                Award Recipient :
                Categories
                Article
                Custom metadata
                © The Author(s) 2020

                Uncategorized
                viral pathogenesis,virus-host interactions
                Uncategorized
                viral pathogenesis, virus-host interactions

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