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
Salgado, Vanessa R; Queiroz, Artur T L de; Sanabani, Sabri S et al. (2016) The microbiological signature of human cutaneous leishmaniasis lesions exhibits restricted bacterial diversity compared to healthy skin. Mem Inst Oswaldo Cruz 111:241-51
Christensen, Stephen M; Dillon, Laura A L; Carvalho, Lucas P et al. (2016) Meta-transcriptome Profiling of the Human-Leishmania braziliensis Cutaneous Lesion. PLoS Negl Trop Dis 10:e0004992
Guimarães, Luiz H; Saldanha, Maíra; Menezes, Taís et al. (2015) A Potential Role for Mononuclear Phagocytes in Cutaneous Ulcer Development in Human Immunodeficiency Virus-Leishmania braziliensis Coinfection. Am J Trop Med Hyg 93:1219-23
Novais, Fernanda O; Scott, Phillip (2015) CD8+ T cells in cutaneous leishmaniasis: the good, the bad, and the ugly. Semin Immunopathol 37:251-9
Fleming, Bryan D; Chandrasekaran, Prabha; Dillon, Laura A L et al. (2015) The generation of macrophages with anti-inflammatory activity in the absence of STAT6 signaling. J Leukoc Biol 98:395-407
Sousa, Louisa M A; Carneiro, Matheus B H; Dos Santos, Liliane M et al. (2015) IL-18 contributes to susceptibility to Leishmania amazonensis infection by macrophage-independent mechanisms. Cytokine 74:327-30
Passos, Sara; Carvalho, Lucas P; Costa, Rúbia S et al. (2015) Intermediate monocytes contribute to pathologic immune response in Leishmania braziliensis infections. J Infect Dis 211:274-82
Novais, Fernanda O; Carvalho, Lucas P; Passos, Sara et al. (2015) Genomic profiling of human Leishmania braziliensis lesions identifies transcriptional modules associated with cutaneous immunopathology. J Invest Dermatol 135:94-101
Cardoso, Thiago Marconi; Machado, Álvaro; Costa, Diego Luiz et al. (2015) Protective and pathological functions of CD8+ T cells in Leishmania braziliensis infection. Infect Immun 83:898-906
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

Showing the most recent 10 out of 15 publications