Leishmaniasis encompasses a complex of diseases with diverse clinical outcomes that include localized or widespread cutaneous, mucosal and visceral syndromes. The majority of people infected with Leishmania control infection and remains asymptomatic. However, the mechanisms that medicate control infection and whether there is parasite clearance are not known. American tegumentary leishmaniasis (ATL) due to L. braziliensis evolves with a biased immune response to parasite antigens manifested by high TNF? and INF? but low IL-10. In contrast, visceral leishmaniasis (VL) presents with high levels of IL-10 and TNF? and low levels of INF?. In recent studies we have shown that IL6 and loci controlling the wound healing response are associated with tegumentary leishmaniasis, and that HLA is associated with the outcome of L. i. chagasi infection. We hypothesize that the clinical spectrum of Leishmania infections is determined by immune responses regulated locally at the site of infection and reflected in the periphery, providing potential biomarkers for disease progression or recovery. Major emphases of this proposal will be address the contrasts between the outcomes of infection with different species of Leishmania and the human host responses. We propose to study novel pathways of gene expression that are influenced by major genetic risk factors, allowing us to progress to the identification of signatures that will predict disease outcome that can be applied clinically in the management or prevention of disease. The major goals of this study are: (1) To determine the downstream pathways regulated by host genes shown to influence VL and ATL through transcriptional profiling of infected tissues and peripheral blood; (2) To understand the functional correlates and epigenetic regulation of IL6 and FLU in ATL; and (3) To identify the immunologic mechanisms determining the different phenotypes in L. i. chagasi-infection and to define whether variability in host immune response to Leishmania antigens is due to HLA. These studies will provide infonmation about novel targets for therapeutic intervention by delineating the mechanisms that lead to parasite control and clearance and by identifying molecular signatures in the blood or infected tissues that can be targeted.
This study will focus on the mechanisms of protection and repair during L. braziliensis and L. i. chagasi infection. The results will advance our understanding ofthe immunogenetic basis ofthe clinical phenotypes of leishmaniasis and identify targets for therapeutic intervention and prophylaxis.
|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|
|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:|
|Gimblet, Ciara; Meisel, Jacquelyn S; Loesche, Michael A et al. (2017) Cutaneous Leishmaniasis Induces a Transmissible Dysbiotic Skin Microbiota that Promotes Skin Inflammation. Cell Host Microbe 22:13-24.e4|
|Almeida, Lucas; Silva, Juliana A; Andrade, Viviane M et al. (2017) Analysis of expression of FLI1 and MMP1 in American cutaneous leishmaniasis caused by Leishmania braziliensis infection. Infect Genet Evol 49:212-220|
|Weirather, Jason L; Duggal, Priya; Nascimento, Eliana L et al. (2017) Comprehensive candidate gene analysis for symptomatic or asymptomatic outcomes of Leishmania infantum infection in Brazil. Ann Hum Genet 81:41-48|
|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|
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