Leishmania braziliensis is the most important causal agent of cutaneous leishmaniasis (CL) and mucosal leishmaniasis (ML) in South American. Additionally, in 19S6 we reported a new clinical form of leishmaniasis called disseminated leishmaniasis (DL). DL is defined by the sudden development of a febrile illness in an individual with a primary ulcer and the appearance of 10 and up to 1000 acneiform papules and ulcerated lesions spanning the whole body. DL is of growing concern because of the increasing number of cases in the last 20 years, from 0.2% to 4% in Northeastern Brazil, the presence of a large number of lesions, the occurrence of mucosal disease in up to 40% of the patients, and a high rate of failure to therapy. L. braziliensis is polymorphic and isolates that cause DL have genotypic characteristics different from CL and ML. Additionally parasites isolated from DL induce higher production of pro- inflammatory chemokines and TNF in macrophages than CL isolates. The histopathologic findings in DL are similar to CL with few parasites, lymphocyte infiltration and granuloma formation. Moreover we have not detected any impairment of macrophages in leishmania killing and no impairment in T cells response in DL. In contrast macrophages from DL produce higher levels of TNF, CXCL9 and CXCL 1O than CL cells. We have also demonstrated that CDS cytolytic T cells mediate increased pathology in CL patients and metastasis in L. brazi/iensis infection. It is known that inflammation plays a key role in metastasis in cancer. Our hypothesis is that an exaggerated inflammatory response mediated by macrophages and CDS T cells leads to metastasis and pathology in DL.
In Aim1 of this project, we will determine the host and parasite factors that lead to DL, and based upon this knowledge propose new and effective methods of treatment.
In Aim1 we will characterize parasite and vector factors in DL. We will determine if parasites from primary ulcer differ from those of metastasis lesions, and if parasites from patients with 10-12 lesions differ from these obtained from patients with more than 5 lesions. We will also determine if phlebotomies species in the area of cases of DL will be different from sandflies isolated from the environment of patients with CL. In the Aim 2 we will assess the contribution of monocytes and macrophages to the exaggerated inflammatory response and metastasis of L. braziliensis infected cells. In the Aim 3 we will define the participation of CDS+ T cells in the inflammatory response and metastasis observed in DL infected cells.

Public Health Relevance

Disseminated leishmaniasis (DL) is a severe form of leishmaniasis highly associated with failure to therapy. DL is not due a poor immune response but rather to an exaggerated inflammatory response. Defining the cells and molecules that cause inflammation in DL will allow us to develop therapies to decrease this deleterious response and improve responses to therapy.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project--Cooperative Agreements (U01)
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Special Emphasis Panel (ZAI1)
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Rao, Malla R
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Federal University of Bahia
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Lopes, Diego Mota; de Almeida, Tarcísio Vila Verde S; de Souza, Robson da Paixão et al. (2018) Susceptibility of dendritic cells from individuals with schistosomiasis to infection by Leishmania braziliensis. Mol Immunol 93:173-183