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.
|ConceiÃ§Ã£o, Jacilara; Davis, Richard; Carneiro, Pedro Paulo et al. (2016) Characterization of Neutrophil Function in Human Cutaneous Leishmaniasis Caused by Leishmania braziliensis. PLoS Negl Trop Dis 10:e0004715|
|de Oliveira Mendes-Aguiar, C; Vieira-GonÃ§alves, R; GuimarÃ£es, L H et al. (2016) Effector memory CD4(+) T cells differentially express activation associated molecules depending on the duration of American cutaneous leishmaniasis lesions. Clin Exp Immunol 185:202-9|
|Carneiro, Pedro Paulo; ConceiÃ§Ã£o, Jacilara; Macedo, Michael et al. (2016) The Role of Nitric Oxide and Reactive Oxygen Species in the Killing of Leishmania braziliensis by Monocytes from Patients with Cutaneous Leishmaniasis. PLoS One 11:e0148084|
|Weirather, Jason L; Duggal, Priya; Nascimento, Eliana L et al. (2016) Fine mapping under linkage peaks for symptomatic or asymptomatic outcomes of Leishmania infantum infection in Brazil. Infect Genet Evol 43:1-5|
|Oliveira, Joyce Moura; RÃªgo, Jamile LeÃ£o; de Lima Santana, Nadja et al. (2016) The -308 bp TNF gene polymorphism influences tumor necrosis factor expression in leprosy patients in Bahia State, Brazil. Infect Genet Evol 39:147-54|
|Muniz, Aline C; Bacellar, OlÃvia; Lago, Ednaldo Lima et al. (2016) Immunologic Markers of Protection in Leishmania (Viannia) braziliensis Infection: A 5-Year Cohort Study. J Infect Dis 214:570-6|
|Schaut, Robert G; Lamb, Ian M; Toepp, Angela J et al. (2016) Regulatory IgDhi B Cells Suppress T Cell Function via IL-10 and PD-L1 during Progressive Visceral Leishmaniasis. J Immunol 196:4100-9|
|Carvalho, Augusto M; Amorim, Camila F; Barbosa, Juliana L S et al. (2015) Age modifies the immunologic response and clinical presentation of American tegumentary leishmaniasis. Am J Trop Med Hyg 92:1173-7|
|Esch, Kevin J; Schaut, Robert G; Lamb, Ian M et al. (2015) Activation of autophagy and nucleotide-binding domain leucine-rich repeat-containing-like receptor family, pyrin domain-containing 3 inflammasome during Leishmania infantum-associated glomerulonephritis. Am J Pathol 185:2105-17|
|Gimblet, Ciara; Loesche, Michael A; Carvalho, Lucas et al. (2015) IL-22 Protects against Tissue Damage during Cutaneous Leishmaniasis. PLoS One 10:e0134698|
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