Human infection with species of the Leishmania genus causes a wide range of disease manifestations ranging 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 severe form mucosal leishmaniasis, whereas Leishmania chagasi is responsible for visceral leishmaniasis. The outcome of either L. braziliensis and L. chagasi infections can include self-resolution, or they can evolve into clinically apparent and severe disease. Mucosal leishmaniasis patients have a biased immune response to parasite antigens manifested by high TNF-oc and IFN-y but low IL-10 production, and decreased responsiveness to suppression by IL-10 and TGF-p. In contrast, VL patients present with high levels of IL-10 and TNF-a and low levels of INF-y The major goals of this project are to identify genes involved in susceptibility/resistance to distinct clinical forms of leishmaniasis.
The specific aims of this project are: (1) To strengthen linkage findings of VL population. New multiplex will be used for fine mapping studies to localize the genes, supplemented by family based association analysis that incorporates information from simplex families. (2) To expand candidate genes and their role in determining risk of ML among families ascertained through cutaneous or mucosal leishmaniasis cases (3.) To examine autosomal SNP markers genotyped for this 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 will incorporate this admixture information into the analytical strategy. Since the general Brazilian population is a mixture of three major racial groups (European, African and Amerindian), formal admixture analysis should provide a better test for genes controlling risk to different clinical outcomes of Leishmania infection. We hope at the end of the study to have a better understanding of innate human immune factors involved in determining the severity of disease due to the Leishmania species. Such knowledge may reveal arms of the immune system that are important for cure.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Specialized Center (P50)
Project #
5P50AI030639-18
Application #
8113443
Study Section
Special Emphasis Panel (ZAI1)
Project Start
Project End
Budget Start
2010-07-01
Budget End
2011-06-30
Support Year
18
Fiscal Year
2010
Total Cost
$195,344
Indirect Cost
Name
Federal University of Bahia
Department
Type
DUNS #
900845397
City
Salvador
State
Country
Brazil
Zip Code
40110-160
Sousa, Rosana; Andrade, Viviane M; Bair, Thomas et al. (2018) Early Suppression of Macrophage Gene Expression by Leishmania braziliensis. Front Microbiol 9:2464
Silva, Silvana C; Guimarães, Luiz Henrique; Silva, Juliana A et al. (2018) Molecular epidemiology and in vitro evidence suggest that Leishmania braziliensis strain helps determine antimony response among American tegumenary leishmaniasis patients. Acta Trop 178:34-39
Novais, Fernanda O; Carvalho, Augusto M; Clark, Megan L et al. (2017) CD8+ T cell cytotoxicity mediates pathology in the skin by inflammasome activation and IL-1? production. PLoS Pathog 13:e1006196
Cincurá, Carolina; de Lima, Clara Mônica F; Machado, Paulo R L et al. (2017) Mucosal leishmaniasis: A Retrospective Study of 327 Cases from an Endemic Area of Leishmania (Viannia) braziliensis. Am J Trop Med Hyg 97:761-766
Carvalho, Augusto M; Fukutani, Kiyoshi F; Sharma, Rohit et al. (2017) Seroconversion to Lutzomyia intermedia LinB-13 as a biomarker for developing cutaneous leishmaniasis. Sci Rep 7:3149
Davis, Richard E; Sharma, Smriti; Conceição, Jacilara et al. (2017) Phenotypic and functional characteristics of HLA-DR+ neutrophils in Brazilians with cutaneous leishmaniasis. J Leukoc Biol 101:739-749
Teixeira, D G; Monteiro, G R G; Martins, D R A et al. (2017) Comparative analyses of whole genome sequences of Leishmania infantum isolates from humans and dogs in northeastern Brazil. Int J Parasitol 47:655-665
Lima, Josivan Gomes; Nobrega, Lucia Helena C; Lima, Natalia Nobrega et al. (2017) Normal bone density and trabecular bone score, but high serum sclerostin in congenital generalized lipodystrophy. Bone 101:21-25
Lima, Ádila L M; de Lima, Iraci D; Coutinho, José F V et al. (2017) Changing epidemiology of visceral leishmaniasis in northeastern Brazil: a 25-year follow-up of an urban outbreak. Trans R Soc Trop Med Hyg 111:440-447
Kelly, Patrick H; Bahr, Sarah M; Serafim, Tiago D et al. (2017) The Gut Microbiome of the Vector Lutzomyia longipalpis Is Essential for Survival of Leishmania infantum. MBio 8:

Showing the most recent 10 out of 85 publications