mycolactone diffuses from mycobacterium ulcerans–infected tissues and targets mononuclear cells in peripheral blood and lymphoid organs从分枝杆菌细菌内酯扩散ulcerans-infected组织和目标在外周血单核细胞和淋巴器官.pdfVIP

Mycolactone Diffuses from Mycobacterium ulcerans– Infected Tissues and Targets Mononuclear Cells in Peripheral Blood and Lymphoid Organs 1 2 2 2 1 Hui Hong , Emmanuelle Coutanceau , Marion Leclerc , Laxmee Caleechurn , Peter F. Leadlay , Caroline Demangel2* ´ ´ ´ ´ 1 University of Cambridge, Department of Biochemistry, Cambridge, United Kingdom, 2 Institut Pasteur, UP Pathogenomique Mycobacterienne Integree, Paris, France Abstract Background: Buruli ulcer (BU) is a progressive disease of subcutaneous tissues caused by Mycobacterium ulcerans. The pathology of BU lesions is associated with the local production of a diffusible substance, mycolactone, with cytocidal and immunosuppressive properties. The defective inflammatory responses in BU lesions reflect these biological properties of the toxin. However, whether mycolactone diffuses from infected tissues and suppresses IFN-c responses in BU patients remains unclear. Methodology/Principal Findings: Here we have investigated the pharmacodistribution of mycolactone following injection in animal models by tracing a radiolabeled form of the toxin, and by directly quantifying mycolactone in lipid extracts from internal organs and cell subpopulations. We show that subcutaneously delivered mycolactone diffused into mouse peripheral blood and accumulated in internal organs with a particular tropism for the spleen. When mice were infected subcutaneously with M. ulcerans, this led to a comparable pattern of distribution of mycolactone. No evidence that mycolactone circula