Between vigilance and tolerance: Innate immune signaling at the intestinal epithelium
Final Report Abstract
Although not all aims of the original project proposal could be reached, significant progress has been made in our understanding of the structural and functional mechanisms that establish and maintain the intestinal mucosal barrier in the continuous presence of commensal bacteria and enteropathogenic microorganisms. In particular, we have gained significant insight in the kinetic of the postnatal intestinal barrier maturation in respect to the delivery of mucosal antigens to the underlying immune cell compartments, the critical and cooperative role of the mucus layer and secreted antimicrobial peptides forming a physicochemical shield, the presence and nature of the homeostatic innate immune signaling at the intestinal epithelium and the conditions that facilitate innate immune stimulation during challenge with enteropathogenic microorganisms and thus allow an efficient antimicrobial host defence. We will further pursue the topic in future studies in particular in respect to antigen delivery and immune cell maturation by luminal antigens during the postnatal period and the functional features during pathogen exposure (both at the microbial and host side) that promote and impede an efficient antimicrobial host response. With this work, we hope to better understand the development of food allergies early in life and identify strategies to improve oral vaccination. Also, we aim at identifying therapeutic approaches to foster the neonatal mucosal immune system to prevent or better protect from enteric infection and reduce the morbidity and mortality from enteric infection in children.
Publications
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Generation of mouse small intestinal epithelial cell lines that allow the analysis of specific innate immune functions. PLoS One, 8(8): e72700, 2013
Schwerk, J,. Köster, M., Hauser, H., Rohde, M., Fulde, M., Hornef, M.W., May, T.
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IFIT2 mediates type I IFN signal amplification and LPS-induced endotoxin shock. J Immunol. 191(7): 3913-21, 2013
Siegfried, A., Berchtold, S., Manncke, B., Deuschle, E., Ott, T., Pott, J., Stockinger, S., Kalinke, U., Hofer, M.J., Gailus-Durner, V., Fuchs, H., Hrabě de Angelis, M., Hornef, M.W., Autenrieth, I.B. and Bohn, E.
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Age-dependent enterocyte invasion and microcolony formation by Salmonella. PLoS Pathog. 10(9): e1004385, 2014
Zhang, K., Dupont, A., Torow, N., Gohde, F., Leschner, S., Lienenklaus, S., Weiss, S., Brinkmann, M.M., Kühnel, M., Hensel, M., Fulde., M., Hornef, M.W.
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Interleukin 13-induced Paneth cell degranulation and antimicrobial peptide release. J. Innat Immun. 6: 530-541, 2014
Stockinger, S., Albers, T., Ménard, S., Dürr, C.U., Pütsep, K., Andersson, M., Dupont, A., Hornef, M.W.
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TRIF determines intestinal epitelial homeostasis but is compensated during mucosal repair. J Immunol. 193: 4223-34, 2014
Stockinger, S., Duerr, C.U., Dolowschiak, T., Fulde, M.,Pott, J., Yang, I., Eibach, D., Bäckhed, F., Akira, S., Suerbaum, S., Brugman, M., Hornef, M.W.
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Active suppression of intestinal CD4+TCRαβ+ T lymphocyte maturation during the postnatal period. Nat Commun. 6: 7725, 2015
Torow, N., Yu, K., Hassani, K., Bleich, A., Lochner, M., Brenneke, A., Weiss, S., Förster, R., Pabst, O., Hornef, M.W.
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Caspase-8 is essential to maintain intestinal barrier function in response to mucosal pathogens through permission of inflammatory shedding. Gut. 64: 601-10, 2015
Günther, C., Buchen, B., He, G-W., Torow, N., Neumann, H., Wittkopf, N., Martini E., Hornef, M.W., Bleich, A., Neurath, MF and Becker, C.
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Dedicated immunosensing of the mouse intestinal epithelial barrier facilitated by a pair of genetically coupled lectin-like receptors. Mucosal Immunol. 8: 232-42, 2015
Leibelt, S., Friede, M., Rohe C., Gütle, D., Weigert, A, Hornef, M.W. and Steinle A.
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Intestinal mucus-affinity and biological activity of an orally administered antibacterial and anti-inflammatory peptide. Gut, 64: 222-32, 2015
Dupont A, Kaconis Y, Yang I, Woltemate S, Heinbockel L, Andersson M, Suerbaum S, Brandenburg K, Hornef MW
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Transcriptional profiling of intestinal CD4+ T cells in the neonatal and adult mice. Genomics Data, 5: 371-374, 2015
Torow, N., Dittrich-Breiholz, O., Hornef, M.W.
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Viral dsRNA (poly (I:C)) induces necrotizing enterocolitis in neonatal mice. Pediatr Res. 79(4):596-602, 2016
Ginzel, M., Yu, Y., Feng, X., von Wasielewski, R., Hornef, M.W., Vieten, G., Klemann, C., Torow, N., Ure, B.M., Kuebler, J.F., Lacher, M.
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Gut Colonization by Methanogenic Archaea Is Associated with Organic Dairy Consumption in Children. Front Microbiol. 8:355, 2017
van de Pol JA, van Best N, Mbakwa CA, Thijs C, Savelkoul PH, Arts IC, Hornef MW, Mommers M, Penders J
