International Mammalian Genome Society

logo18th International Mouse Genome Conference

17-22 October 2004, Seattle, USA


POSTER 87- AN IN VIVO ENU MUTAGENESIS SCREEN TO IDENTIFY CYTOMEGALOVIRUS-SUSCEPTIBILITY GENES.

Crozat K, Georgel P, Hoebe K, Du X, Tabeta K, Beutler B

TSRI, La Jolla, United States

Natural Killer (NK) cells play a crucial role in the innate mechanisms directed against viral infections. Mice represent a convenient and well established in vivo model to study the antiviral functions of NK cells, as antibody depletion of these cells leads to severe susceptibility to the Mouse Cytomegalovirus (MCMV, a double-stranded DNA Herpes-family virus). Recently, the Ly49H receptor was shown to be of central importance in MCMV susceptibility. The Ly49H gene (which is absent in the MCMV-sensitive BALB/c strain) encodes a C-type lectin-transmembrane receptor which associates to an accessory factor, DAP12, containing an Immunoreceptor Tyrosine-based Activating Motif (ITAM) to promote target cell lysis. The ligand of the Ly49H receptor is the MCMV-encoded protein m157, which supports the idea that this receptor mediates a specific innate immune response against viruses. In addition, dendritic cells (DC) have been shown to produce type I interferons (IFN) in response to viral infections, thereby assisting the NK-dependent response that eliminates the pathogen. In order to provide a better understanding of the innate immune response against viral infections, we designed an in vivo screen of EthylNitrosoUrea (ENU) mutated MCMV-resistant (C57BL/6) mice and searched for animals with abnormal susceptibility to MCMV infection. A total of 17 MCMV-sensitive lines have been derived from this screen. In addition, we have shown that Toll-like Receptors (TLR) signaling is essential for an efficient anti-viral response, as evidenced by low cytokine production, high mortality rate and increased splenic viral titer upon viral challenge of Tlr9, Tlr3, MyD88 and Trif mutants. We have also identified a coat color mutant, “salt and pepper” (spp), with enhanced susceptibility to MCMV infection.

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