07-ABSTRACT All pathogens that cause chronic infections must avoid clearance by the host immune response. Many have complex mechanisms to rapidly generate diversity in critical antigens. Mycobacterium tuberculosis chronically infects one third of the worlds'population and similarly must avoid clearance by the host immune system. However, there is currently little understanding of whether M. tuberculosis, like so many other pathogens, diversifies in vivo to escape host immune selection. In this proposal, we will test the hypothesis that M. tuberculosis varies, either genetically or epigenetically, during the course of infection and that this variation contributes to the ability of the bacteria to avoid clearance by the host immune response. We will use new genomics technologies?low cost genome sequencing and expression profiling?to systematically assess genetic and epigenetic variation in bacteria selected in a simple experimental model of disease chosen to create different immune pressures on the bacteria ?mice of different MHC haplotypes. In these studies, we expect to provide fundamental insights into the mechanisms and targets of diversifying immune selection in M. tuberculosis.
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