International Mammalian Genome Society

17th International Mouse Genome Conference

9-12 November 2003, Braunschweig, Germany


PLENARY PRESENTATION

WEDNESDAY 12 NOVEMBER
09:00 – 09:30 HRS

MUTAGENESIS IN THE DISSECTION OF INNATE IMMUNE SENSING PATHWAYS

Bruce Beutler
The Scripps Research Institute

Innate immune sensing in mammals depends largely upon a collection of molecules known as the Toll-like receptors (TLRs), which bind specific molecular components of microbes and initiate a host response. A spontaneous mutation (affecting the Lps locus in mice, and positionally identified in our laboratory as a mutation in Tlr4) first revealed the sensing function of the TLRs, and we have since ENU to disrupt additional molecular components of the TLR signaling apparatus, monitoring macrophage responses to diverse microbial inducers. Of twelve TLRs encoded in the mouse genome, LPS TLR3 senses dsRNA, while TLR4 senses LPS. Lps2, a mutation identified in an F3 germline mutant, was shown to disrupt responses mediated by both receptors. The mutation was positionally identified in Trif, a gene encoding one of five adapter proteins for TLR signal transduction. TrifLps2 impairs responses to both viral and bacterial pathogens. Moreover, the mutation revealed that there are two “branches” of the LPS signaling pathway, which depend upon a total of four of the adapter proteins. While the TrifLps2 allele, produced on the C57BL/6 background, permitted dsRNA-induced upregulation of costimulatory molecules for antigen presentation, the Trifθ allele, produced on a 129 strain background, did not. This strain-related difference in responses to dsRNA was mapped to a single locus on chromosome 7 (dsRNA1), and marks an accessory pathway for dsRNA sensing, independent of Trif or TLR3. Two additional ENU-induced mutations that ablate peptidoglycan sensing (Pgn1 and Pgn2) appear to mark novel component(s) of a pathway for bacterial detection. Hence, a number of new and important components of the afferent innate immune system have been revealed through analysis of macrophage responses, and additional screens, probing resistance to authentic infections, may reveal still others.


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