Leishmaniasis is a major public health problem in Brazil, and we propose experiments that will advance our understanding of this disease with the goal of more effective disease control. This project involves collaborations between the Universities of Pennsylvania and Maryland in the USA, and the University of Bahia in Brazil. L. braziliensis infection is associated with a strong inflammatory response that is the major factor in causing disease. Patients with L. braziliensis exhibit a pronounced increase in circulating proinflammatory monocytes, suggesting that these cells contribute to the severe pathologic inflammatory response observed in these patients. To obtain fundamental information about the role of myeloid-lineage cells in this disease, we will evaluate circulating and tissue-localized myeloid cells at a phenotypic and functional level in cutaneous leishmaniasis patients in Brazil. We will also determine if the relative frequency of proinflammatory monocytes and/or levels of their secreted products serve as predictive biomarkers of treatment success. If our studies indicate that proinflammatory monocytes play a causative role in the disease progression, it would provide a convincing rationale for the development of new immunotherapies specifically targeting proinflammatory effectors for L. braziliensis patients. We hypothesize that the expansion of proinflammatory monocytes, and their subsequent differentiation into dendritic cells within lesions, results in the excess production of inflammatory cytokines and chemokines that recruit additional T cells and monocytes to the lesion. To address this hypothesis, we will phenotypically and functionally characterize both circulating monocytes (Aim 1) and the myeloid-lineage populations in the lesion (Aim 2) of leishmaniasis patients.
In Aim 3 we will directly test if either proinflammatory monocytes or their secreted products serve as useful biomarkers in disease progression and response to therapy in early cutaneous leishmaniasis. These studies will enhance our basic understanding of the biology of human monocytes, and allow us to apply that information to better develop strategies to control cutaneous leishmaniasis.

Public Health Relevance

Leishmaniasis is a debilitating disease which in Brazil is associated with an exaggerated inflammatory response. The proposed studies will determine whether monocytes contribute to the inflammatory response, and will test if monitoring these cells or their products will be useful predictors of successful treatment.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01AI088650-02
Application #
8197000
Study Section
Special Emphasis Panel (ZAI1-GSM-M (J2))
Program Officer
Rao, Malla R
Project Start
2010-12-01
Project End
2015-11-30
Budget Start
2011-12-01
Budget End
2012-11-30
Support Year
2
Fiscal Year
2012
Total Cost
$601,620
Indirect Cost
$91,642
Name
University of Pennsylvania
Department
Pathology
Type
Schools of Veterinary Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
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Novais, Fernanda O; Nguyen, Ba T; Beiting, Daniel P et al. (2014) Human classical monocytes control the intracellular stage of Leishmania braziliensis by reactive oxygen species. J Infect Dis 209:1288-96
Brito, Graça; Dourado, Mayra; Polari, Ludmila et al. (2014) Clinical and immunological outcome in cutaneous leishmaniasis patients treated with pentoxifylline. Am J Trop Med Hyg 90:617-20
Campos, Taís M; Passos, Sara T; Novais, Fernanda O et al. (2014) Matrix metalloproteinase 9 production by monocytes is enhanced by TNF and participates in the pathology of human cutaneous Leishmaniasis. PLoS Negl Trop Dis 8:e3282
Novais, Fernanda O; Carvalho, Lucas P; Graff, Joel W et al. (2013) Cytotoxic T cells mediate pathology and metastasis in cutaneous leishmaniasis. PLoS Pathog 9:e1003504
Vieira, E L M; Keesen, T S L; Machado, P R et al. (2013) Immunoregulatory profile of monocytes from cutaneous leishmaniasis patients and association with lesion size. Parasite Immunol 35:65-72
Giudice, Angela; Vendrame, Celia; Bezerra, Caroline et al. (2012) Macrophages participate in host protection and the disease pathology associated with Leishmania braziliensis infection. BMC Infect Dis 12:75