Human Buruli ulcer disease (BUD) is a severe skin disease caused by predominantly extracellular infection with Mycobacterium ulcerans (MU). This emergent, high-morbidity disease causes destructive skin ulcers that may cover up to 15% of the body surface area. Secondary infection of the ulcers is extremely rare. Effective treatment requires multiple surgical excisions and skin grafting that often results in significant deformity or disability. Infection of the hairless guinea pig (GP) with virulent MU mimics BUD. The PI has shown that pre-infection exposure to ultraviolet -B (UV) exacerbates BUD and suppresses delayed-type hypersensitivity (DTH) responses to MU in the GP model. The PI has also demonstrated that topical pre- infection exposure to cis-urocanic acid (cUCA), an initiator of photoimmunosuppression, mimics the effects of UV on BUD. A key pathway in UV-induced immunosuppression is the cUCA-neuropeptide pathway. The relevance of this pathway to the effects of UV on infectious disease in general, and BUD in particular, is unknown. This represents a critical gap in the knowledge base. Thus, the aim of this proposal is to test the hypothesis that blocking of the UV-cUCA-neuropeptide-photoimmunosuppression pathway will prevent UV- induced enhancement of MU infection in the hairless guinea pig model of Buruli ulcer disease. To test our hypothesis, 2 experiments will be performed: (1) does pre-irradiation capscaicin-mediated neuropeptide depletion block UV-augmentation of BUD?; and (2) does pre- and post-irradiation treatment with calcitonin gene related peptide receptor antagonists or H1 and H2 histamine antagonists or indomethacin block UV- augmentation of BUD. Importantly, the incorporation of relevant control groups in the proposed experiments will allow for the examination of the role of the neuropeptide-histamine-prostanoid pathway during the pathogenesis of MU infection in non-irradiated animals. Irrespective of the outcomes of these experiments, new and important information on BUD pathogenesis will be obtained.