The major hypothesis of this project is that the control of leishmaniasis in individuals with sub-clinical L.braziliensis infection is performed by innate immune response and that skin associated cytokines and CD8+ T cells participate of tissue damage leading development of cutaneous leishmaniasis (CL), mucosal leishmaniasis and disseminated leishmaniasis (DL). The major aims are:
Aimi) To determine how innate cells control L. braziliensis parasites. Our finding that a large number of individuals (subclinical) who are infected by L.braziliensis will control the parasites without developing disease provides a unique opportunity to define how natural resistance may be occurring to L.braziliensis. We propose to: a) define the mechanism(s) involved in the killing of parasites by neutrophils and macrophages;b) determine if neutrophils and macrophages from patients with different forms ofthe disease exhibit differences in their capacity to kill parasites;
Aim2) To determine what skin-associated cytokines contribute to the pathologic responses following L. braziliensis infecfion. We found that thymic stromal lymphopoietin (TSLP), a cytokine produced by epithelial cells at barrier surfaces, is highly expressed in the epidermis of lesions from CL pafients. We propose to: a) determine the effect of TSLP in macrophage and dendritic cells (DCs) infected with L. braziliensis;b) determine the role of TSLP in CD4+ T and CD8+ T cell proliferation and funcfion;and c) correlate the expression of TSLP in lesions from different clinical phenotypes with T cell function.
Aim3) To determine how CD8 T cells participate in the immunopathology in patients infected with L. braziliensis. Since our preliminary data indicate that CD8 T cells exhibit increased levels of granzyme as the lesions worsen, we hypothesize that CD8 T cells contribute to the pathology seen in patients, and propose to: a) determine the mechanisms involved in the recruitment of CD8+ T cells to cutaneous lesion sites;b) determine the frequency and the balance of inflammatory versus regulatory CD8+ T cell subpopulations in the blood and lesions from CL patients;and c) compare the ability of CD8+ T cells from SC individuals and CL patients to promote killing of L. braziliensis infected macrophages in vitro.
The studies will shift our thinking on how both protection and immunopathology occurs following infecfion with L. braziliensis, will advance our understanding ofthe various clinical forms of human leishmaniasis in Brazil, and will provide informafion that can be applied to develop new approaches to control L.braziliensis infections.
|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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