Myeloid-lineage cells and immunopathology in Leishmania braziliensis

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DESCRIPTION (provided by applicant): 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.