The role of Tregs and lipid mediators in the progression of Mycobacterium leprae infection to active disease

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Mycobacterium leprae, the causative agent of leprosy, is a highly infectious obligate intracellular bacterium. The vast majority of the individuals exposed to M. leprae becomes infected, but only a small proportion of the infected individuals evolves to active disease. Previous work in leprosy and tuberculosis demonstrated a major role of interferon-γ, an effector cytokine produced by pathogen-specific memory CD4 T cells, in the control of the infection by these intracellular pathogens. Our preliminary data show a progressive reduction in M. leprae-specific IFNγ levels in individuals that correlates to indicators of level of exposure to M. leprae and to bacillary load in individuals with leprosy. When we evaluated the interaction of M. leprae with Schwann cells and mononuclear phagocytes, we observed an induction of the anti-inflammatory cytokine IL-10 and the lipid mediator PGE-2. Metabolomics analyses of lesions and sera from leprosy patients also demonstrated clear differences in the presence of polyunsaturated fatty acid (PUFA) derived lipid mediators that correlated to the clinical forms of leprosy and bacillary loads. Other investigators detected frequencies of Foxp-3 positive T cells in the blood and lesions of leprosy patients that correlate to the expected inhibition of cellular immunity and effector function against M. leprae in the multibacillary forms of leprosy. Taking in to account these findings, we hypothesize that M. leprae interactions with Schwann cells and mononuclear phagocytes generate a microenvironment via the activities of lipid mediator that facilitates the inhibition of pathogen-specific IFN-γ response by Treg. We will test these hypotheses in the experiments of the following specific aims: 1-Evaluate the phenotype and functionally the Treg present in the blood and skin lesions of M. leprae-infected individuals and leprosy patients, to define the role of Treg in Th1 regulation during leprosy disease. 2- Investigate specific lipid mediators of inflammatory and immune responses and their alteration of the immune responses in M. leprae- infected individuals. Negative regulation of the immune response entails several different mechanisms that are present but less visible in asymptomatic individuals in the initial stages of the silent, long-evolving steps of chronic infections, autoimmune diseases, and cancer. Looking at changes in regulatory T responses that precede the onset of active disease using epidemiological and functional data as clues has the potential for reducing the individual and economic costs associated to these major health problems.