Abstract
Infection of human skin with Mycobacterium ulcerans, the causative agent of Buruli ulcer, is associated with the systemic diffusion of a bacterial macrolide named mycolactone. Patients with progressive disease show alterations in their serum proteome, likely reflecting the inhibition of secreted protein production by mycolactone at the cellular level. Here, we used semi-quantitative metabolomics to characterize metabolic perturbations in serum samples of infected individuals, and human cells exposed to mycolactone. Among the 430 metabolites profiled across 20 patients and 20 healthy endemic controls, there were significant differences in the serum levels of hexoses, steroid hormones, acylcarnitines, purine, heme, bile acids, riboflavin and lysolipids. In parallel, analysis of 292 metabolites in human T cells treated or not with mycolactone showed alterations in hexoses, lysolipids and purine catabolites. Together, these data demonstrate that M. ulcerans infection causes systemic perturbations in the serum metabolome that can be ascribed to mycolactone. Of particular importance to Buruli ulcer pathogenesis is that changes in blood sugar homeostasis in infected patients are mirrored by alterations in hexose metabolism in mycolactone-exposed cells.
Highlights
Cohort 1 Age, median, years Sex, no
To further explore the physiological consequences of bacterial production of mycolactone in infected hosts, we compared the metabolic perturbations induced by infection with M. ulcerans in human hosts to those induced by mycolactone treatment in human cells
Jurkat T cells were selected as a model, because leukocytes are exposed to mycolactone during M. ulcerans infection[15,16], and Jurkat T cells display the same functional defects as primary T cells upon exposure to mycolactone in vitro[17,18,19]
Summary
Cohort 1 Age, median (range), years Sex, no. Male/no. Femelle Ulcer category I (lesion size ≤ 5 cm in widest diameter) II (lesion size ≤ 15 cm in widest diameter) Cohort 2 Age, median (range), years Sex, no. Its precise mechanism of action remains to be elucidated, there is recent evidence that mycolactone blocks the co-translational translocation of secreted and membrane-bound proteins into the endoplasmic reticulum[21,22]. In line with this finding, the proteomic profiling of serum samples of patients with BU showed significant reductions in the level of multiple soluble proteins, including T cell cytokines[23]. In addition to provide novel insight into the molecular mechanisms underlying BU pathogenesis, our study delineates mycolactone signature in the serum metabolome of infected hosts
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