03051nas a2200397   4500000000100000008004100001260000900042653001200051653002600063653001900089653001700108653001800125653002700143653002300170653001500193653002200208653000900230653002400239653002700263653001300290653001700303100001300320700001600333700001500349700001200364700001500376700002300391700001400414245014700428856007700575300001000652490000600662050001500668520195600683022001402639       2013                            d  c201310aAnimals10aAnti-Bacterial Agents10aBacterial Load10aBuruli ulcer10aCell Survival10aDisease Models, Animal10aHistocytochemistry10aMacrolides10aMass Spectrometry10aMice10aMice, Inbred BALB C10aMycobacterium ulcerans10aRifampin10aStreptomycin1 aSarfo FS1 aConverse PJ1 aAlmeida DV1 aZhang J1 aRobinson C1 aWansbrough-Jones M1 aGrosset J00aMicrobiological, histological, immunological, and toxin response to antibiotic treatment in the mouse model of Mycobacterium ulcerans disease.  uhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC3597478/pdf/pntd.0002101.pdf  ae21010 v7  aSARFO 20133 a<p>Mycobacterium ulcerans infection causes a neglected tropical disease known as Buruli ulcer that is now found in poor rural areas of West Africa in numbers that sometimes exceed those reported for another significant mycobacterial disease, leprosy, caused by M. leprae. Unique among mycobacterial diseases, M. ulcerans produces a plasmid-encoded toxin called mycolactone (ML), which is the principal virulence factor and destroys fat cells in subcutaneous tissue. Disease is typically first manifested by the appearance of a nodule that eventually ulcerates and the lesions may continue to spread over limbs or occasionally the trunk. The current standard treatment is 8 weeks of daily rifampin and injections of streptomycin (RS). The treatment kills bacilli and wounds gradually heal. Whether RS treatment actually stops mycolactone production before killing bacilli has been suggested by histopathological analyses of patient lesions. Using a mouse footpad model of M. ulcerans infection where the time of infection and development of lesions can be followed in a controlled manner before and after antibiotic treatment, we have evaluated the progress of infection by assessing bacterial numbers, mycolactone production, the immune response, and lesion histopathology at regular intervals after infection and after antibiotic therapy. We found that RS treatment rapidly reduced gross lesions, bacterial numbers, and ML production as assessed by cytotoxicity assays and mass spectrometric analysis. Histopathological analysis revealed that RS treatment maintained the association of the bacilli with (or within) host cells where they were destroyed whereas lack of treatment resulted in extracellular infection, destruction of host cells, and ultimately lesion ulceration. We propose that RS treatment promotes healing in the host by blocking mycolactone production, which favors the survival of host cells, and by killing M. ulcerans bacilli.</p>  a1935-2735