colitis; innate mucosal immunity; inflammation restitution; commensal microbial mutualism; infectious enteropathy; innate lymphoid cells; intestinal mononuclear cells
Gomez de Aguero M., Ganal-Vonarburg S. C., Fuhrer T., Rupp S., Uchimura Y., Li H., Steinert A., Heikenwalder M., Hapfelmeier S., Sauer U., McCoy K. D., Macpherson A. J. (2016), The maternal microbiota drives early postnatal innate immune development, in Science
, 351(6279), 1296-1302.
Von Burg N, Chappaz S, Baerenwaldt A, Horvath E, Dasgupta SB, Ashok D, Pieters J, Tacchini-Cottier F, Rolink H, Acha-Orbea H, Finke D (2014), Activated group 3 innate lymphoid cells promote T-cell-mediated immune responses, in PNAS
, (35), 12835-12840.
Sellin M.A, Müller A.A, Felmy B, Dolowschiak T, Diard M, Tardivel A, Maslowski K.M, Hardt W.D. (2014), Epithelium-intrinsic NAIP/NLRC4 inflammasome drives expulsion of infected enterocytes to restrict Salmonella replication in the intestinal mucosa, in Cell Host & Microbe
, (2), 237.
Thelemann Christoph, Eren Remzi Onur, Coutaz Manuel, Brasseit Jennifer, Bouzourene Hanifa, Rosa Muriel, Duval Anais, Lavanchy Christine, Mack Vanessa, Mueller Christoph, Reith Walter, Acha-Orbea Hans (2014), Interferon-gamma Induces Expression of MHC Class II on Intestinal Epithelial Cells and Protects Mice from Colitis, in PLOS ONE
, (1), e86844.
Bjerrum JT, Nielsen OH, Riis LB, Pittet V, Mueller C, Rogler G, Olsen J (2014), Transcriptional Analysis of Left-sided Colitis, Pancolitis, and Ulcerative Colitis-associated Dysplasia, in Inflamm Bowel Dis
, (20(12)), 2340.
Weber Benjamin, Schuster Steffen, Zysset Daniel, Rihs Silvia, Dickgreber Nina, Schurch Christian, Riether Carsten, Siegrist Mark, Schneider Christoph, Pawelski Helga, Gurzeler Ursina, Ziltener Pascal, Genitsch Vera, Tacchini-Cottier Fabienne, Ochsenbein Adrian, Hofstetter Willy, Kopf Manfred, Kaufmann Thomas, Oxenius Annette, Reith Walter, Saurer Leslie, Mueller Christoph (2014), TREM-1 Deficiency Can Attenuate Disease Severity without Affecting Pathogen Clearance, in PLOS PATHOGENS
, (1), e1003900.
Diard Médéric, Sellin Mikael E., Dolowschiak Tamas, Arnoldini Markus, Ackermann Martin A., Hardt Wolf Dietrich (2013), Antibiotic treatment selects for cooperative virulence of salmonella typhimurium, in Current Biology
, (17), 2000-2005.
Stecher B, Maier L, Hardt Wolf-Dietrich (2013), 'Blooming' in the gut: how dysbiosis might contribute to pathogen evolution, in Nat Rev Microbiol
Maier Lisa, Vyas Rounak, Cordova Carmen Dolores, Lindsay Helen, Schmidt Thomas, Brugiroux Sandrine, Periaswamy Balamurugan, Bauer Rebekka, Sturm Alexander, Schreiber Frank, von Mering Christian, Robinson Mark D, Stecher Bärbel, Hardt Wolf-Dietrich (2013), Microbiota-driven Hydrogen Fuels Salmonella Typhimurium Invasion of the gut Ecosystem, in Cell Host & Microbe
Kaiser P, Regoes R.R, Dolowschiak T, Wotzka S, Lengefeld J, Slack E, Grant A.J, Ackermann M, Hardt Wolf-Dietrich, Cecum lymph node dendritic cells harbor slow-growing bacteria phenotypically tolerant to antibiotic treatment, in PLoS Biology
Maier L, Diard M, Sellin M.E, Chouffane E.S, Trautwein-Weidner K, Periaswamy B, Slack E, Dolowschiak T, Stecher B, Loverdo C, Regoes R.R, Hardt W.D., Granulocytes Impose a Tight Bottleneck upon the Gut Luminal Pathogen Population during Salmonella Typhimurium Colitis, in PLoS Pathogens
Mammals harbor a dense and complex microbial community in their intestines. Under homeostasis, this microbiota lives mutualistically within the host. A dense network of interactions (microbes-microbes, microbes-host, host-microbes) affects the composition of the microbiota as well as most aspects of host physiology producing homeostasis, especially at the level of the intestinal mucosa. The cellular and molecular mechanisms maintaining mucosal homeostasis are incompletely understood. Nonetheless, they are of crucial importance to understand the basic biology of the homeostatic interactions, to identify mechanisms allowing host-microbial systems to return to homeostasis upon challenge and to elucidate how disease results when homeostatic mechanisms fail, such as in Crohn’s disease or ulcerative colitis.Analysis of the mechanisms maintaining mucosal homeostasis has been hampered by our incomplete understanding of the cellular mechanisms of the intestinal immune system and by the sheer complexity of this biology. The “microbiota” is composed of 500-1500 microbial species, most of which have not been analyzed. Thus, key stimuli affecting mucosal homeostasis remain poorly defined. Model systems with reduced complexity are therefore of great importance.We propose to develop axenic mouse models (totally lacking microbes) and gnotobiotic mice associated with a defined gut flora composed of eight isolated strains of the altered Schädler flora (ASF mice) to study mucosal immune responses that restore homeostasis after exposure to microbial or immunological challenge. This will be achieved by:1.Generation of axenic and ASF-associated wild type and knockout mice.2.Use of axenic and ASF-mice to develop models for transient challenge by commensals (HA107), pathogens (S. Typhimurium), or immune dysregulation. These models will enable systematic study of the mechanisms driving recovery of mucosal homeostasis after challenge3.Analyze the generation, activation and effector functions of key regulatory cells of the mucosal immune system, including innate lymphoid cells (LTi, NKR LTi, NK, nuocytes), regulatory T-cells and intestinal mononuclear phagocytes (CX3CR1hi/lo macrophages, CD103+CD11b+/- dendritic cells, CD11c+E-cadherin+ phagocytes).4.Analyze the role of protective antibodies and of T cell contraction in attenuating intestinal inflammation.5.Analyze the role of mucosal desensitization, in particular, of the intestinal epithelial cells6.Demonstrate the functional importance of the identified mechanisms for re-establishing mucosal homeostasis in vivo using transgenic and knockout mice, cell depletion strategies, adoptive cell transfer.This project can only be tackled by the collaborative added value, specialized resources and infrastructure of the four synergistic laboratories: i.e. A. Macpherson, a world-leader in mucosal immunology who has established a unique facility for generating and handling axenic and gnotobiotic mice; ii. C. Mueller, an international expert in mouse IBD models and the studies of Treg- and intestinal mononuclear cell function; iii. D. Finke, an international expert in the development and function of LTi cells; and iv. W.-D. Hardt, an international expert in gut infection models for Salmonella enteropathy. The technologies, resources and findings resulting from this work will be of fundamental importance for the field and will define the mechanisms re-establishing mucosal homeostasis after challenge. We speculate that defects in these mechanisms will also be causally involved in the induction and exacerbation of inflammatory bowel disease.