Müller: Biomodelling of Listeriosis in Mice
State of the Art:
Intracellular pathogens usually take advantage of a host cell surface molecule in order to enter the interior. Species barriers and differences to infection in natural conditions (low dose and route of infection) between mice and man can be overcome by ‘humanizing’ the mouse genome, i.e. introducing and/or altering the species-specific pathogen interacting/entry genes. In a collaborative effort with the Helmholtz Zentrum für Infektionsforschung (Braunschweig, Germany, Siggi Weiss) we have generated knock-in mice carrying humanized E-cadherin alleles. E-cadherin facilitates the host cell internalization of the foodborne pathogen Listeria monocytogenes (L.m.). In a second approach a collection of immuno-compromised – interferon signaling impaired – mice will be utilized to unravel the molecular host-pathogen differences between standard laboratory L.m. strains and L.m. strains collected from food chain samples or clinics (collaboration with Martin Wagner, Department for Farm Animals and Veterinary Public Health).
Key Hypotheses:
(i) Humanized mice will provide an important tool for studying the course and mechanisms of ‘infection’ compared to ‘challenge’. (ii) In vivo infections of wildtype and mutant mice will shed light on the differing molecular patho-mechanisms of laboratory and ‘field’ isolates of L.m. in the host environment. (iii) Vice versa, L.m. infections of mutant mice and cells significantly contribute to the identification of the molecular networks required for L.m. defence.
Methodological Approaches:
Mice (wildtype, gene-targeted and ‘humanized’) will be orally challenged (high-dose) or infected (low dose) with different L.m. strains and survival and host responses will be monitored. Host cellular and molecular contributions to the outcome of bacterial exposure will be assayed in in vitro systems.
Publication List
- Stockinger, S., Kastner, R., Kernbauer, E., Pilz, A., Westermayer, S., Reutterer, B., Soulat, D., Stengl, G., Vogl, C., Frenz, T., Waibler, Z., Taniguchi, T., Rulicke, T., Kalinke, U., Muller, M. and Decker, T. (2009). Characterization of the Interferon-Producing Cell in Mice Infected with Listeria monocytogenes. PLoS Pathog. 5, e1000355.
- Reutterer, B., Stockinger, S., Pilz, A., Soulat, D., Kastner, R., Westermayer, S., Rulicke, T., Muller, M., and Decker, T. (2008). Type I IFN are host modulators of strain-specific Listeria monocytogenes virulence. Cell. Microbiol. 10, 1116-1129.
- Weichhart, T., Costantino, G., Poglitsch, M., Rosner, M., Zeyda, M., Stuhlmeier, K. M., Kolbe, T., Stulnig, T. M., Hörl, W. H., Hengstschläger, M., Müller, M., and Säemann, M. (2008). The TSC2/mTOR pathway regulates the innate inflammatory response. Immunity 29, 565-577.
- Lassnig, C., Sanchez, C.M., Egerbacher, M., Walter, I., Majer, S., Kolbe, T., Pallares, P., Enjuanes, L., Müller, M. (2005) Development of a transgenic mouse model susceptible to human coronavirus 229E. Proc. Natl. Acad. Sci. USA 102, 8275-8280.
- Strobl, B., Bubic, I., Bruns, U., Steinborn, R., Lajko, R., Kolbe, T., Karaghiosoff, M., Kalinke, U., Jonjic, S., Müller, M. (2005). Novel functions of Tyk2 in the antiviral defense against murine cytomegalovirus. J. Immunol. 175, 4000-4008.