MAPPING OF GENETIC MODULATORS OF NATURAL-RESISTANCE TO INFECTION WITHSALMONELLA-TYPHIMURIUM IN WILD-DERIVED MICE

Despite antibiotic therapy and vaccination programs, microbial disease s continue to be the leading cause of morbidity and mortality worldwid e. The genetic basis of the host response to infection is complex, and its understanding has been facilitated through the study of mouse mod els of human infectious diseases. Genetic variation in resistance of m ice to infection with Salmonella typhimurium has been recognized for o ver 50 years and shown to be a multifactorial trait. We have studied t he genetic basis of resistance or susceptibility to infection with S. typhimurium in the wild-derived inbred mouse Mus musculus molossinus ( MOLF/Ei). MOLF/Ei mice are extremely susceptible to infection with S. typhimurium despite the presence of resistance alleles at Nramp1 and L ps. To identify genes that modulate the expression of natural resistan ce or susceptibility to infection with S. typhimurium in MOLF/Ei, we h ave performed a genome-wide study using an F2 intercross between C56BL /6J and MOLF/Ei inbred mice. We have mapped three QTLs that significan tly affect survival time following lethal infection with S. typhimuriu m. The Salmonella-resistant phenotype was linked to Nramp1 on proximal chromosome 1 (maximum lod score of 18.8 at D1Mcg4) and to a newly map ped region on mouse chromosome 11 (maximum lod score of 7.0 at D11Mit5 ). The third QTL conferred recessive susceptibility and was located on mouse chromosome 1, approximately 25 cM distal to Nramp1 (maximum lod score of 4.8 at D1Mit100). (C) 1908 Academic Press.