Exploring TrpB in the pathogenesis of cryptosporidiosis

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 DESCRIPTION (provided by applicant): Cryptosporidiosis is a diarrheal disease that disproportionately affects children and immunocompromised adults. The WHO estimates that in 2010, diarrheal disease accounted for 10.5% of deaths in children under the age of five, with the majority of childhood deaths occurring in Africa and Southeast Asia. In developing countries, malnutrition exacerbates diarrheal episodes and prolongs infection. These prolonged childhood infections are known to cause destructive, permanent effects, such as stunted growth, developmental delay, and cognitive deficiency. Of the known diarrheal diseases, cryptosporidiosis appears to one of the most deadly. Tryptophan synthesis enables intracellular bacteria such as Mycobacterium tuberculosis and Chlamydia trachomatis to evade a key mechanism of host innate immunity, IFN-γ induced tryptophan catabolism. Through horizontal gene transfer, Cryptosporidium has acquired a bacterial tryptophan synthase gene, tryptophan synthase beta (CpTrpB), and we believe that this gene acquisition was a crucial step to adaptation to the mammalian intestine. We will evaluate the role of CpTrpB in Cryptosporidium metabolism, growth, and survival during host tryptophan catabolism. In this project we propose to 1) define the metabolic activity of CpTrpB during host tryptophan catabolism, both in vitro and in vivo, and 2) determine the impact of CpTrpB gene loss on Cryptosporidium parvum through genetic analysis. The unique tryptophan metabolism in Cryptosporidium is an attractive target for drug development and pathogen attenuation, and studying CpTrpB offers the opportunity to explore the biology of a novel parasite pathogenesis factor.