International Mammalian Genome Society

logo18th International Mouse Genome Conference

17-22 October 2004, Seattle, USA


POSTER 86 - ISOLATION OF GENES IMPLICATED IN INNATE IMMUNE RESPONSE AGAINST LISTERIA MONOCYTOGENES USING ENU MUTAGENESIS SCREENING IN THE MOUSE

Rutschmann S, Du X, Huser N, Jiang Z, Hoebe K, Beutler B

The Scripps Research Institute, La Jolla, CA, United States

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 models 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 implemented a screen for germline mutant mice with enhanced susceptibility to Listeria infection. Mice were inoculated intravenously with Listeria and closely monitored for signs of illness. A total of 4319 mice have been screened, allowing us to isolate 9 transmissible mutations in genes that specifically disrupt the mouse resistance to Listeria. All phenodeviants identified were bred, and the progeny tested to ascertain transmissibility of the mutations. 3 of these mutant lines have been established as homozygous stocks, and are currently being outcrossed for positional cloning. Meanwhile, these mutant mice are subjected to detailed phenotypic analysis, including neutrophils counts and activity studies, inflammatory cytokine production following an infection with Listeria, macrophage phagocytic activity and cytokine production in response to various other stimuli.

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