Metabolomic profiles delineate mycolactone signature in Buruli ulcer disease

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.

Blood serum metabolome of atopic dermatitis: Altered energy cycle and the markers of systemic inflammation

“…The peptide discovered from the untargeted analysis in this study— is a cleavage peptide of Fibrinogen A-α. The increase in the concentration of named peptide is not specific to atopic dermatitis but has also been seen in Buruli ulcer [ 32 ], tuberculosis [ 33 ] and diabetes [ 34 ]. The properties of fibrin clot in AD patients’ blood samples have been studied and the analysis revealed an increased clot mass and fiber thickness, faster clot formation among other altered plasma fibrin clot properties [ 35 ].…”

The Immunology of Buruli Ulcer

“…More extensive multi-analyte profiling of serum proteins in BU patients and endemic controls revealed that, although the disease does not influence significantly the leukocyte composition of the peripheral blood, it impacts an even wider array of circulating molecules [31,66]. Indeed, several of these analytes contribute to acute phase reaction, metabolism, coagulation and tissue remodeling, with some of them already having been implicated in healing speed [31,66]. Specifically regarding metabolic factors, M. ulcerans not only interferes with energy-generation, but also with peptide, lipid and nucleotide pathways [66].…”

“…Indeed, several of these analytes contribute to acute phase reaction, metabolism, coagulation and tissue remodeling, with some of them already having been implicated in healing speed [31,66]. Specifically regarding metabolic factors, M. ulcerans not only interferes with energy-generation, but also with peptide, lipid and nucleotide pathways [66]. Even though many of these alterations seem to be in line with the expected response of the host to infectious processes, others, as the proposed impairment of the tricarboxylic acid (TCA) cycle, could be the result of a direct effect of mycolactone [66,67].…”

“…Specifically regarding metabolic factors, M. ulcerans not only interferes with energy-generation, but also with peptide, lipid and nucleotide pathways [66]. Even though many of these alterations seem to be in line with the expected response of the host to infectious processes, others, as the proposed impairment of the tricarboxylic acid (TCA) cycle, could be the result of a direct effect of mycolactone [66,67]. In reality, among TCA cycle intermediates, patients with BU have decreased citrate levels, whose relevance in other infectious diseases is associated with generating prostaglandins, nitric oxide and other antimicrobial peptides [66,67].…”

Genetics in the Host‐Mycobacterium ulcerans interaction

“…117 The core of M. ulcerans-induced lesions becomes consequently bursting with dying cells, with milder effects being observed as it spreads regionally and systemically to more distant organs. [118][119][120][121] The metabolism of M. ulcerans also presents important nuances that influence its pathogenesis. M. ulcerans growth is optimal at 32°C, explaining the lack of systemic dissemination of the infection in BU patients.…”