International Mammalian Genome Society

17th International Mouse Genome Conference

9-12 November 2003, Braunschweig, Germany


POSTER 213 - ISOLATION OF GENES IMPLICATED IN IMMUNE RESPONSES AGAINST INTRACELLULAR PATHOGENS USING ENU MUTAGENESIS SCREENING IN THE MOUSE

Rutschmann S
The Scripps Research Institute, La Jolla

Co-Authors: Du X, Beutler B
Institutions: The Scripps Research Institute, La Jolla

Infectious diseases are a leading cause of morbidity and mortality worldwide. It is known that genetic variation foretells susceptibility to many of these diseases in both humans and animals. Thus, the positional identification of genes that are critical for host defense against infections looms as one of the greatest challenges in immunology. The intracellular bacterium Listeria monocytogenes is one of the most studied model for such infections. Resistance to this pathogen relies on both innate and adaptive immunity, but many aspects of our defenses are still not completely understood. To gain deeper insight into the nature of these immune responses, infectious agents need to be considered in the context of their complex mammalian host. For this reason, an in vivo forward genetic approach has been undertaken. We have therefore implemented a screen for germline mutant mice with enhanced susceptibility to Listeria infection. 6 to 8 week old mice are inoculated intravenously with a standardized dose of Listeria, a quantity non lethal for wild type mice, but lethal for mutant animals. Mice are then closely monitored following inoculation for signs of illness. All phenodeviants identified in this manner are bred to ascertain transmissibility and mice with transmissible mutations are subjected to comprehensive phenotypic analysis and positional cloning. A total of 3866 mice, consisting of 1631 F1 and 2235 F3 animals carrying dominant and recessive mutations respectively, have been tested so far. Our screen recently allowed us to isolate three transmissible mutations in genes that specifically disrupt the mouse resistance to Listeria.


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