1. The Citrobacter rodentium type III secretion system effector EspO affects mucosal damage repair and antimicrobial responses
- Author
-
James C. Wright, Nicolas Serafini, Gad Frankel, Eran Elinav, James P. Di Santo, Meirav Pevsner-Fischer, Cedric N. Berger, Valerie F. Crepin, Theodoros I. Roumeliotis, Jyoti S. Choudhary, Lu Yu, Medical Research Council Centre for Molecular Bacteriology and Infection [Londres, Royaume-Uni] (MRC CMBI), Imperial College London, Division of Cancer Biology [Londres, Royaume-Uni], The institute of cancer research [London], Immunité Innée - Innate Immunity, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Immunology [Rehovot, Israël], Weizmann Institute of Science [Rehovot, Israël], This project was supported by grant MR/K019007/1 awarded by the medical research council UK (https://mrc.ukri.org), by grants WT098051 and 107057/Z/15/Z awarded by the Wellcome Trust (https://wellcome.ac.uk/) and by grant 695467 – ILC_REACTIVITY awarded by the European Research Council (https://erc.europa.eu)., European Project: 695467,H2020-EU.1.1. - EXCELLENT SCIENCE - European Research Council (ERC) ,ILC_REACTIVITY(2016), Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Bodescot, Myriam, and Biological Determinants of ILC Reactivity for Immune Responses in Health and Disease - ILC_REACTIVITY - - H2020-EU.1.1. - EXCELLENT SCIENCE - European Research Council (ERC) 2016-08-01 - 2021-07-31 - 695467 - VALID
- Subjects
0301 basic medicine ,Pulmonology ,Neutrophils ,Physiology ,Secretion Systems ,Pathology and Laboratory Medicine ,Biochemistry ,Type three secretion system ,Mice ,White Blood Cells ,Intestinal mucosa ,Animal Cells ,Microbial Physiology ,Citrobacter rodentium ,Type III Secretion Systems ,Medicine and Health Sciences ,Bacterial Physiology ,Biology (General) ,Intestinal Mucosa ,Post-Translational Modification ,Phosphorylation ,Immune Response ,Effector ,Innate lymphoid cell ,Enterobacteriaceae Infections ,3. Good health ,[SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology ,Cell Processes ,[SDV.IMM]Life Sciences [q-bio]/Immunology ,Female ,Anatomy ,Cellular Types ,Pathogens ,Research Article ,[SDV.IMM] Life Sciences [q-bio]/Immunology ,QH301-705.5 ,Colon ,Virulence Factors ,Immune Cells ,030106 microbiology ,Immunology ,Biology ,digestive system ,Microbiology ,03 medical and health sciences ,Immune system ,Virology ,Tissue Repair ,Genetics ,Animals ,Secretion ,[SDV.MP] Life Sciences [q-bio]/Microbiology and Parasitology ,Molecular Biology ,Cell Proliferation ,Innate immune system ,Blood Cells ,Biology and Life Sciences ,Proteins ,Bacteriology ,Cell Biology ,RC581-607 ,Immunity, Innate ,Mice, Inbred C57BL ,Gastrointestinal Tract ,030104 developmental biology ,Respiratory Infections ,Parasitology ,Immunologic diseases. Allergy ,Physiological Processes ,Digestive System ,Antimicrobial Cationic Peptides - Abstract
Infection with Citrobacter rodentium triggers robust tissue damage repair responses, manifested by secretion of IL-22, in the absence of which mice succumbed to the infection. Of the main hallmarks of C. rodentium infection are colonic crypt hyperplasia (CCH) and dysbiosis. In order to colonize the host and compete with the gut microbiota, C. rodentium employs a type III secretion system (T3SS) that injects effectors into colonic intestinal epithelial cells (IECs). Once injected, the effectors subvert processes involved in innate immune responses, cellular metabolism and oxygenation of the mucosa. Importantly, the identity of the effector/s triggering the tissue repair response is/are unknown. Here we report that the effector EspO ,an orthologue of OspE found in Shigella spp, affects proliferation of IECs 8 and 14 days post C. rodentium infection as well as secretion of IL-22 from colonic explants. While we observed no differences in the recruitment of group 3 innate lymphoid cells (ILC3s) and T cells, which are the main sources of IL-22 at the early and late stages of C. rodentium infection respectively, infection with ΔespO was characterized by diminished recruitment of sub-mucosal neutrophils, which coincided with lower abundance of Mmp9 and chemokines (e.g. S100a8/9) in IECs. Moreover, mice infected with ΔespO triggered significantly lesser nutritional immunity (e.g. calprotectin, Lcn2) and expression of antimicrobial peptides (Reg3β, Reg3γ) compared to mice infected with WT C. rodentium. This overlapped with a decrease in STAT3 phosphorylation in IECs. Importantly, while the reduced CCH and abundance of antimicrobial proteins during ΔespO infection did not affect C. rodentium colonization or the composition of commensal Proteobacteria, they had a subtle consequence on Firmicutes subpopulations. EspO is the first bacterial virulence factor that affects neutrophil recruitment and secretion of IL-22, as well as expression of antimicrobial and nutritional immunity proteins in IECs., Author summary Citrobacter rodentium is a gold standard model to study pathogen-host-microbiome interactions. Two of the hallmarks of C. rodentium infection are colonic damage repair responses and colitis; symptoms that are shared with inflammatory bowel diseases in humans. The processes leading to tissue damage repair responses and the implicated bacterial virulence factors are still elusive. In this paper, we show that the C. rodentium type III secretion system effector EspO plays a major role in triggering damage healing responses, recruitment of neutrophils to the colonic villi, secretion of IL-22 from colonic explants and expression of IL-22 regulated genes in intestinal epithelial cells. This paper is the first to report a bacterial virulence factor that impacts on both intestinal epithelial cell proliferation and immune responses.
- Published
- 2018