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Pamela Small University of Tennessee Knoxville, USA

Mycobacteria ulcerans is an environmental pathogen. What is an environmental pathogen? Humans are irrelevant; no P-P spread: M. avium, M. kansasii, M. marinum. How do you identify the “natural” host? How do you know you’ve found it?. The M. marinum complex

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Pamela Small University of Tennessee Knoxville, USA

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  1. Mycobacteria ulcerans is an environmental pathogen What is an environmental pathogen? Humans are irrelevant; no P-P spread: M. avium, M. kansasii, M. marinum How do you identify the “natural” host? How do you know you’ve found it? The M. marinum complex M. marinum; M.marinum DL clade-fish M. ulcerans-Natural hosts? M. liflandii-frogs (X. tropicalis, X. laevis) M. pseudoshottsii (striped bass) ……AQUATIC ENVIRONMENTS… M. ulcerans genome Reductive evolution 790 pseudo-genes Plasmid-encoded toxin 400 copies IS elements RD1 deletion Pamela Small University of Tennessee Knoxville, USA

  2. Mycobacterium ulcerans disease is toxin mediated Schutte, et al. PLoS NTD 2007 Antibiotic treatment Mycolactone Cell cycle arrest, apoptosis, necrosis

  3. Adusumilli et al, 2005; Demangel, 2006, 2007 Genetics rules… Mycolactone mutants are avirulent but have long term host survival Regulation of mycolactone production? Role in latency, re-occurance? Mycolactone is required for immunosuppression and necrosis in BU

  4. Immunomodulatory properties of mycolactone Transient intracellular stage (humans, mice, gps) dissemination? Th1 response nodule (+) versus ulcer (-) Inhibition of phagocytosis (murine and human macs) Travel to draining lymph node (humans,mice) Lack of acute inflammatory response (humans, gps) Modest granuloma formation Immunomodulatory effects of mycolactone ng amts. blocks maturation of of DCs blocks emigration of skin DCs to lymphnodes (Mice) inhibits activation T cell priming inhibits T cell production of inflammatory molecules abolishes: MIP 1, MIP-1,INF-inducible protein 10 monocyte attractant protein 1, RANTES systemic effects on INF production???? Suppression of innate immune response of DCs prevents traffficking of inflammatory cells to lesions Local and systemic immunosuppression Mycolactone- M. ulcerans PGL equivalent? Nodule INF Ulcer Adusumilli, 2005; Coutanceau et al, 2007

  5. Torrado, et all 2006 MU in mice Acute inflammatory response no granuloma formation lack area of central necrosis Poor CD3 repertoire Lack Il-8 skin architecture thin fat-poor many basophils Mouse model DC maturation, homing macrophage survival apoptotic pathways response to antibiotics? Gaps in our knowledge Route of infection from environment to humans? Reservoir species? Natural Host? Latency? Re-occurance Mycolactone regulation? Cellular target Immunomodulatory mechanisms Pharmokinetics Importance of dermal architecture GP Model Good model for Disease. Lack of reagents and cell lines for studying immune response is a serious limitation

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