Human infection with species of the Leishmania genus causes a wide range of disease manifestationsranging from asymptomatic infection to clinical leishmaniasis, which can be severe and even fatal. In Brazil,Leishmania braziliensis is the most frequent species causing cutaneous leishmaniasis and its more severeform mucosal leishmaniasis, whereas Leishmania chagasi is responsible for visceral leishmaniasis. Theoutcome of either L. braziliensis and L. chagasi infections can include self-resolution, or they can evolve intoclinically apparent and severe disease. Mucosal leishmaniasis patients have a biased immune response toparasite antigens manifested by high TNF-oc and IFN-y but low IL-10 production, and decreasedresponsiveness to suppression by IL-10 and TGF-p. In contrast, VL patients present with high levels of IL-10and TNF-a and low levels of INF-y The major goals of this project are to identify genes involved insusceptibility/resistance to distinct clinical forms of leishmaniasis.
The specific aims of this project are: (1) Tostrengthen linkage findings of VL population. New multiplex will be used for fine mapping studies to localizethe genes, supplemented by family based association analysis that incorporates information from simplexfamilies. (2) To expand candidate genes and their role in determining risk of ML among families ascertainedthrough cutaneous or mucosal leishmaniasis cases (3.) To examine autosomal SNP markers genotyped forthis project in addition to markers on the Y chromosome and mitochondrial DNA in families with mucosal,cutaneous and visceral leishmaniasis to assess the extent of genetic admixture in these populations. We willincorporate this admixture information into the analytical strategy. Since the general Brazilian population is amixture of three major racial groups (European, African and Amerindian), formal admixture analysis shouldprovide a better test for genes controlling risk to different clinical outcomes of Leishmania infection. Wehope at the end of the study to have a better understanding of innate human immune factors involved indetermining the severity of disease due to the Leishmania species. Such knowledge may reveal arms of theimmune system that are important for cure.
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