Metabolomic profiles delineate mycolactone signature in Buruli ulcer disease

International audienceInfection 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. Buruli ulcer (BU) is a necrotizing disease of the skin caused by infection with Mycobacterium ulcerans, the third most prevalent mycobacterial pathogen in humans after M. tuberculosis and M. leprae 1. How M. ulcerans is transmitted to humans is not fully understood, however there is increasing evidence that breaches in the skin barrier and exposure to contaminated environments are both required 2–5. Since the 1980s, BU has spread in low-income developing countries of West Africa 6. If not diagnosed or treated appropriately, it can result in irreversible deformity, functional disability and life-threatening secondary infections. The current diagnosis methods include acid-fast staining, culture or amplification of bacterial DNA from fine needle aspirates, swabs or skin biopsies 7. Treatment consists of the daily administration of rifampicin and streptomycin for eight weeks 8,9 , and excision surgery of large lesions. Although effective, control programs are costly, reactive rather than pro-active, and globally unsuited to field conditions. In order to improve the detection and management of BU, it is essential to improve our understanding of the molecular and cellular mechanisms underpinning BU pathogenesis 10. M. ulcerans is unique amongst human pathogens in its capacity to produce a polyketide-derived macrolide called mycolactone 11–14. Bacterial production of mycolactone is essential for BU formation, as shown by the avirulence of mycolactone-deficient strains of M. ulcerans in rodent models of infection. While bacteria grow primarily in host skin tissues, mycolactone gains access to the peripheral circulation 15,16. Foodpad infection of mice with wild-type, but not mycolactone-deficient strains of M. ulcerans, induced intrinsic defects in blood T cells evidenced by their incapacity to produce cytokine