Enteric (typhoid) fever caused by salmonella species is frequently fatal in man, domestic animals, and rodents. Salmonella serotypes and species exhibit a high degree of host specificity in their ability to cause enteric fever (Salmonella typhi, man; S. derby, cattle; S. pullorum, poultry, and S. enteritidis and S. typhimurium, mice). In the mouse Ity is the major genetic locus affecting salmonella resistance during the first two weeks following oral or parenteral infection. This is accomplished primarily by Ity control of the rate of intracellular growth of salmonella in the liver and spleen of infected mice. Ity has been reported to also affect resistance to intracellular infections with Mycobacterium bovis, Mycobacterium lepraemurium, and Leishmania donovani, but not a number of other intracellular and extracellular pathogens. The mechanism by which Ity controls intracellular growth rates is not known. The salmonella gene mviA(vir) is necessary for certain salmonella to exploit the Ity(s) (susceptible) genotype, but has little or no effect on the growth of salmonella in Ity(r) (resistant) mice. Knowledge of the mechanism of action of mviA should not only provide insight into mechanisms used by salmonella to grow in the host, but may also reveal the mechanism of action of Ity. We have identified a restriction site into which the insertion of antibiotic resistance cassettes blocks mviA function. We have demonstrated that avirulence is the result of a functional mviA(avir) and that insertion of an antibiotic resistance cassette into mviA(avir) results in virulence. From the proposed studies we hope to obtain detailed knowledge about the mviA gene and the nature of its gene product (MviA), and its mechanism of action. We will also continue ongoing studies to identify nutrients and pathways that limit the growth of mviA(vir) and mviA(avir) salmonella in Ity(r) and Ity(s )mice. Anything we learn about rate limiting in vivo growth factors will add to our knowledge of the micro-environment of growing salmonella and should contribute to our studies of mviA and Ity mechanisms, and visa versa. The results of the proposed studies should contribute to our understanding of the regulation of intracellular growth rates of not only salmonella, but certain other intracellular pathogens.
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