We have recently demonstrated that distinct groups of genetically related strains of Leishmania brasiliensis are associated with different clinical forms of leishmaniasis [namely localized cutaneous (CL), disseminated (DL) and mucosal (ML) leishmaniasis) in areas of active disease transmission. Our long term goals, including the current application, are: (1) a better understanding of how the human infection with the different strains of L. brasiliensis results in the different outcomes of leishmaniasis; and (2) the development of tools for the diagnosis of the parasites strains causing human infection, with prognostic value on the disease outcome. The first specific aims of the current application are: (1) detect differences at the DMA level among strains of L. brasiliensis causing CL, DL or ML in a model endemic area of American tegumentary leishmaniasis at northeastern Brazil; and (2) compare the global gene expression profiles among human immune cells infected in vitro with L. brasiliensis strains associated with CL, DL or ML from this same endemic area. To accomplish the first aim we will clone and sequence several regions of the genomes of L. brasiliensis isolates associated with CL, DL or ML, then compare the sequences of corresponding fragments, [unreadable] searching for disease associated mutations (i.e. parasite genetic markers of potential prognostic value on human disease). To accomplish the second aim peripheral blood mononuclear cells samples, belonging to same healthy donors, will be infected with L. brasiliensis isolates associated with CL, DL or ML in vitro, then total RNA will be collected at different time points and the expression of immune and non-immune related genes assessed by micro array, using a human DMA chip, and compared. The results of the micro arrays will be analyzed and compared using specific software packages. The leishmaniasis are a major public health problem with 400 million individuals at risk in tropical and subtropical areas of the globe, an incidence of 600,000 and a prevalence of 12 million cases per year. L. brasiliensis derived CL, DL and ML present diverse responses to the first line treatment with antimonials as well as prognosis. The better understanding of the effects of parasite strains on host cells that lead to the diverse outcomes and the development of tools for the diagnosis of leishmaniasis at the parasite strain level may ultimately lead to improved therapeutics / prophylaxis, and better case management, respectively, with important impact on disease burden. [unreadable] [unreadable]
NIH ExPorter
NIH ExPorter