Combined Inflammatory and Metabolic Defects Reflected by Reduced Serum Protein Levels in Patients with Buruli Ulcer Disease

Abstract

Buruli ulcer is a skin disease caused by Mycobacterium ulcerans that is spreading in tropical countries, with major public health and economic implications in West Africa. Multi-analyte profiling of serum proteins in patients and endemic controls revealed that Buruli ulcer disease down-regulates the circulating levels of a large array of inflammatory mediators, without impacting on the leukocyte composition of peripheral blood. Notably, several proteins contributing to acute phase reaction, lipid metabolism, coagulation and tissue remodelling were also impacted. Their down-regulation was selective and persisted after the elimination of bacteria with antibiotic therapy. It involved proteins with various functions and origins, suggesting that M. ulcerans infection causes global and chronic defects in the host's protein metabolism. Accordingly, patients had reduced levels of total serum proteins and blood urea, in the absence of signs of malnutrition, or functional failure of liver or kidney. Interestingly, slow healers had deeper metabolic and coagulation defects at the start of antibiotic therapy. In addition to providing novel insight into Buruli ulcer pathogenesis, our study therefore identifies a unique proteomic signature for this disease.

Challenges associated with the treatment of Buruli ulcer

“…All lesions were culture positive until 2 weeks but thereafter all were culture negative . Some follow‐up studies have indicated that healing delay may occur in up to two‐thirds of patients within 25 weeks from the start of SR treatment . Sarfo et al.…”

“…Philips et al. subsequently reported that BU patients with active ulcers showed distinctive profile of immune suppression marked by down modulation of selected cytokines and an impaired capacity to produce Th1, Th2, and Th17 cytokines when stimulated with mitogenic agents . Immunohistopathological studies of lesions from BU patients after SR regimen have demonstrated treatment‐associated initiation of vigorous immune responses and the development of ectopic lymphoid tissue in the BU lesions .…”

Sec61 blockade by mycolactone: A central mechanism in Buruli ulcer disease

“…Multi‐analyte profiling of PHA‐stimulated whole blood culture supernatants revealed that in fact, most T cell‐derived cytokines were suppressed during disease progression [Phillips et al., ]. Moreover, patients with BU displayed a distinctive proteomic signature in their serum, marked by a down‐regulation of multiple mediators of inflammation [Phillips et al., , ]. The immunosuppressive signature of BU persisted weeks after completion of antibiotic therapy in treated individuals [Phillips et al., , ], thus correlating with the continued presence of mycolactone.…”

Shaping mycolactone for therapeutic use against inflammatory disorders

“…In addition to a lack of inflammatory infiltrates at the level of skin lesions (7), patients with BU display systemic alterations in their cellular immune responses, evidenced by an impaired capacity of T cells to produce cytokines ex vivo upon stimulation with mitogenic agents (8)(9)(10). Contrary to wild-type strains, mycolactone-deficient mutants of M. ulcerans do not impair the capacity of T cells to produce interleukin-2 (IL-2) in animal models, showing that mycolactone is the cause of these cellular response defects (11).…”