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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Specialized Center (P50)
Project #
7P50AI030639-21
Application #
8501131
Study Section
Special Emphasis Panel (ZAI1-AWA-M)
Project Start
2013-08-01
Project End
2017-07-31
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
21
Fiscal Year
2013
Total Cost
$102,910
Indirect Cost
$7,623
Name
Federal University of Bahia
Department
Type
DUNS #
900845397
City
Salvador
State
Country
Brazil
Zip Code
40110-160
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Castellucci, Léa Cristina; Almeida, Lucas Frederico de; Jamieson, Sarra Elisabeth et al. (2014) Host genetic factors in American cutaneous leishmaniasis: a critical appraisal of studies conducted in an endemic area of Brazil. Mem Inst Oswaldo Cruz 109:279-88
Oliveira, Walker Nonato; Ribeiro, Luís Eduardo; Schrieffer, Albert et al. (2014) The role of inflammatory and anti-inflammatory cytokines in the pathogenesis of human tegumentary leishmaniasis. Cytokine 66:127-32
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LeishGEN Consortium; Wellcome Trust Case Control Consortium 2; Fakiola, Michaela et al. (2013) Common variants in the HLA-DRB1-HLA-DQA1 HLA class II region are associated with susceptibility to visceral leishmaniasis. Nat Genet 45:208-13
Jirmanus, Lara; Glesby, Marshall J; Guimaraes, Luiz H et al. (2012) Epidemiological and clinical changes in American tegumentary leishmaniasis in an area of Leishmania (Viannia) braziliensis transmission over a 20-year period. Am J Trop Med Hyg 86:426-33
Lima, Iraci D; Queiroz, Jose W; Lacerda, Henio G et al. (2012) Leishmania infantum chagasi in northeastern Brazil: asymptomatic infection at the urban perimeter. Am J Trop Med Hyg 86:99-107

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