|Support type:||Scholarships in Brazil - Master|
|Effective date (Start):||February 01, 2009|
|Effective date (End):||August 31, 2009|
|Field of knowledge:||Biological Sciences - Immunology - Applied Immunology|
|Principal Investigator:||Hiro Goto|
|Grantee:||Luana Dias de Souza|
|Home Institution:||Instituto de Medicina Tropical de São Paulo (IMT). Universidade de São Paulo (USP). São Paulo , SP, Brazil|
Leishmaniasis are diseases caused by protozoan of the genus Leishmania that may present as tegumentar and visceral form. In Brazil, American tegumentary leishmanaisis (ATL) is mainly caused by Leishmania (Viannia) braziliensis and cutaneous (CL), mucosal (ML) and disseminated (DL) forms of the disease are known. This diversity of clinical presentations depends on the complex host and parasite interaction ensuing protective and/or lesion promoting immune mechanisms not totally clarified so far. Particularly, virulence factors of the parasite may influence the tissue invasion or inflammatory immune response. In this project we will study a likely diversity of the effect of a growth factor on L. (V.) braziliensis strains isolated from patients presenting different clinical presentations and its relationship to infectivity and/or clinical forms of the disease. L. (V.) braziliensis strains, subjected to species identification in related projets, from patients with detailed clinical follow up presenting CL, ML and DL, from Corte de Pedra municipality, Bahia, will be use d in this study. The initial phase of parasite-host interaction is crucial for the resolution or establishment of the disease where different factors participate including growth factors. A growth factor that has lately drawn attention due to its action and its pleiotropism is the insulin-like growth factor (IGF)-I, filogenetically well preserved, with molecular mass of approximately 7.5 kDa, present in the circulation and in most of tissues, and been produced by cells like hepatocytes, fibroblasts, denditric cells and particularly macrophages. Further, its expression increases during inflammation in the epidermis. Then it been produced by cells that are present in the skin, IGF-I may be one of the first factors encountered by Leishmania in the skin of the host, the initial site of infection. In previous studies of our group we observed that physiological concentrations of IGF-I induces in vitro an increase in the proliferation and phosphorylation of promastigote and amastigote in different Leishmania species, but not IGF-II. In in vivo study in BALB/c mice infected with IGF-I-pre-incubated Leishmania (L.) amazonensis we observed an increase in the lesion size accompanied by the increase in the parasite number in the lesioon, and an increase in the inflammatory infiltrate with IGF-I clearly favoring intracellular parasite growth. In in vitro study, BALB/c mouse macrophages infected with L. (L.) amazonensis promastigotes ad amastigotes IGF-I induced an increase in arginase expression and activity and a decrease in the nitric oxide (NO) production and inducible NO sintase (NOS2). Further IGF-I induced an increase in arginase expression and activity in L. (L.) amazonensis promastigotes ad amastigotes. However study of the participation of IGFI in human leishmaniasis is not known so far. The activity of the enzyme arginase is considered important in the Leishmania-host interaction promoting the increase of polyamine production that are nutrients for the parasite with likely effect on parasitism and infection development. Therefore, we will study, upon IGF-I stimulus arginase expression and activity of L. (V.) braziliensis strains isolated from patients with different clinical presentation, the parasitism and NO production in L. (V.) braziliensis-infected human macrophage cell line THP-1. Further we will relate the arginase activity of IGF-I-reacted Leishmania to the macrophage parasitism and/or clinical presentation of ATL. This study will open a new perspective for better understanding of the pathogeny of human leishmaniasis contributing to the development of prophylactic and therapeutic measures.