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      Mapping of Shigella flexneri’s tissue distribution and type III secretion apparatus activity during infection of the large intestine of guinea pigs

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          ABSTRACT

          Shigella spp. are bacterial pathogens that invade the human colonic mucosa using a type III secretion apparatus (T3SA), a proteinaceous device activated upon contact with host cells. Active T3SAs translocate proteins that carve the intracellular niche of Shigella spp. Nevertheless, the activation state of the T3SA has not been addressed in vivo. Here, we used a green fluorescent protein transcription-based secretion activity reporter (TSAR) to provide a spatio-temporal description of S. flexneri T3SAs activity in the colon of Guinea pigs. First, we observed that early mucus release is triggered in the vicinity of luminal bacteria with inactive T3SA. Subsequent mucosal invasion showed bacteria with active T3SA associated with the brush border, eventually penetrating into epithelial cells. From 2 to 8 h post-challenge, the infection foci expanded, and these intracellular bacteria displayed homogeneously high-secreting activity, while extracellular foci within the lamina propria featured bacteria with low secretion activity. We also found evidence that within lamina propria macrophages, bacteria reside in vacuoles instead of accessing the cytosol. Finally, bacteria were cleared from tissues between 8 and 24 h post-challenge, highlighting the hit-and-run colonization strategy of Shigella. This study demonstrates how genetically encoded reporters can contribute to deciphering pathogenesis in vivo.

          Abstract

          We mapped Shigella flexneri cells and assessed the activity of their type III secretion apparatus in the large intestine of Guinea pigs.

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          Most cited references 40

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          Regional specialization within the intestinal immune system.

          The intestine represents the largest compartment of the immune system. It is continually exposed to antigens and immunomodulatory agents from the diet and the commensal microbiota, and it is the port of entry for many clinically important pathogens. Intestinal immune processes are also increasingly implicated in controlling disease development elsewhere in the body. In this Review, we detail the anatomical and physiological distinctions that are observed in the small and large intestines, and we suggest how these may account for the diversity in the immune apparatus that is seen throughout the intestine. We describe how the distribution of innate, adaptive and innate-like immune cells varies in different segments of the intestine and discuss the environmental factors that may influence this. Finally, we consider the implications of regional immune specialization for inflammatory disease in the intestine.
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            Bacterial invasion: the paradigms of enteroinvasive pathogens.

            Invasive bacteria actively induce their own uptake by phagocytosis in normally nonphagocytic cells and then either establish a protected niche within which they survive and replicate, or disseminate from cell to cell by means of an actin-based motility process. The mechanisms underlying bacterial entry, phagosome maturation, and dissemination reveal common strategies as well as unique tactics evolved by individual species to establish infection.
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              A sentinel goblet cell guards the colonic crypt by triggering Nlrp6-dependent Muc2 secretion.

              Innate immune signaling pathways contribute to the protection of host tissue when bacterially challenged. Colonic goblet cells are responsible for generating the two mucus layers that physically separate the luminal microbiota from the host epithelium. Analysis of colonic tissues from multiple mouse strains allowed us to identify a "sentinel" goblet cell (senGC) localized to the colonic crypt entrance. This cell nonspecifically endocytoses and reacts to the TLR2/1, TLR4, and TLR5 ligands by activating the Nlrp6 inflammasome downstream of TLR- and MyD88-dependent Nox/Duox reactive oxygen species synthesis. This triggers calcium ion-dependent compound exocytosis of Muc2 mucin from the senGC and generates an intercellular gap junction signal; in turn, this signal induces Muc2 secretion from adjacent goblet cells in the upper crypt, which expels bacteria. Thus, senGCs guard and protect the colonic crypt from bacterial intruders that have penetrated the inner mucus layer.
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                Author and article information

                Journal
                Pathog Dis
                Pathog Dis
                femspd
                Pathogens and Disease
                Oxford University Press
                2049-632X
                03 October 2019
                October 2019
                03 October 2019
                : 77
                : 7
                Affiliations
                [1 ] Unité de Pathogénie Microbienne Moléculaire, Institut Pasteur , INSERM U1202, 24-28 rue du Docteur-Roux, 75015 Paris, France
                [2 ] Laboratory for Optical and Computational Instrumentation, University of Wisconsin-Madison, Laboratory for Optical and Computational Instrumentation , 271 Animal Sciences, 1675 Observatory Drive, Madison, WI 53706, USA
                [3 ] Ultrastructural Bioimaging unit, Institut Pasteur , 24-28 rue du Docteur-Roux, 75015 Paris, France
                [4 ] Chaire de Microbiologie et Maladies Infectieuses, Collège de France , 11 Place Marcelin Berthelot, 75231 Paris, France
                [5 ] Architecture et Réactivité de l'ARN, Université de Strasbourg , CNRS UPR9002, 2 Allée Konrad Roentgen, 67084 Strasbourg, France
                [6 ] Unité Pathogenèse des Infections Vasculaires, Institut Pasteur , 24-28 rue du Docteur-Roux, 75015 Paris, France
                [7 ] The Host-Microbe Interactions Laboratory, Department of Chemistry and Biomolecular Sciences, University of Ottawa , 150 Louis-Pasteur private, Ottawa, ON, K1N 6N5, Canada
                [8 ] Department of Biochemistry, Microbiology and Immunology, University of Ottawa , 451 Smyth Rd, Ottawa, ON, K1N 6N5, Canada
                Author notes
                Corresponding author: 150 Louis-Pasteur private, Ottawa, ON, K1N6N5, Canada. Tel: 613-562-5800; E-mail: fcampbel@ 123456uottawa.ca
                Article
                ftz054
                10.1093/femspd/ftz054
                6920510
                31578543
                © FEMS 2019.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@ 123456oup.com

                Page count
                Pages: 9
                Product
                Funding
                Funded by: European Research Council 10.13039/501100000781
                Funded by: Howard Hughes Medical Institute 10.13039/100000011
                Funded by: Canadian Institutes of Health Research 10.13039/501100000024
                Award ID: 159517
                Categories
                Research Article

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