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 TNFa and INFy but low IL-10. In contrast, visceral leishmaniasis (VL) presents with high levels of IL-10 and TNFa and low levels of INFy. 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.

Public Health Relevance

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.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Specialized Center (P50)
Project #
Application #
Study Section
Special Emphasis Panel (ZAI1-AWA-M)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Federal University of Bahia
Zip Code
Conceição, 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-Gonçalves, R; Guimarães, 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; Conceição, 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; Rêgo, Jamile Leão; 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, Olívia; 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

Showing the most recent 10 out of 69 publications