Mycobacterium tuberculosis (MTB) and human immunodeficiency virus (HIV) are two pathogens that have developed a terrifyingly successful relationship. Tuberculosis accounts for up to a third of AIDS-related deaths worldwide, and nearly one quarter of deaths from TB occur in the context of HIV co-infection. It is the rampant spread of HIV among populations with a high incidence of latent TB infection that has spawned this global catastrophe. The overall focus of the research proposed here is to further the understanding of the development and maintenance of latent TB infection within the context of the tuberculous granuloma. Specifically, the aims of this work are to identify the genes of MTB that are specifically required to survive in vitro conditions postulated to occur within the tuberculous granuloma as well as identify genes required to survive within the granuloma itself. The vehicle of discovery is a powerful technology developed in this laboratory over the past two years in which pools of genetically defined mutants of MTB are screened for survival of a particular stress, either in vitro or in vivo. The surviving members of the pool are identified utilizing transposon site hybridization with custom-designed microarrays. This technology has already been used in this lab to identify non-essential MTB genes that are necessary for survival in the murine TB infection model. Since mice do not produce tuberculous granuloma similar to those found in man, the latter parts of this project will utilize the rabbit model of TB. The mutants failing to survive either the in vitro or in vivo granuloma conditions will be compared to wild type and complemented MTB strains for the ability to form caseating granuloma in the rabbit infection model. The identification of MTB genes required for formation of and survival within granuloma is the first step in the development of new drugs to specifically treat latently-infected TB patients, which in turn will help to curtail mortality of TB as well as HIV.
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