Immunosuppressive Signature of CutaneousMycobacterium ulceransInfection in the Peripheral Blood of Patients with Buruli Ulcer Disease

Abstract

Buruli ulcer disease (BUD) is an emerging human disease caused by infection with Mycobacterium ulcerans, which leads to the development of necrotic skin lesions. The pathogenesis of the ulcer is closely associated with the production of mycolactone, a diffusible cytotoxin with immunomodulatory properties. To identify immunological correlates of BUD, we performed a broad screen of inflammatory mediators in serum samples and stimulated whole-blood supernatants of patients. We found that patients with active ulcers displayed a distinctive profile of immune suppression, marked by the down-modulation of selected chemokines and an impaired capacity to produce Th1, Th2, and Th17 cytokines on stimulation with mitogenic agents. These immunological defects were induced early in the disease and resolved after anti-BUD therapy, establishing their association with the presence of M. ulcerans. Interestingly, some of the defects in cytokine and chemokine response could be mimicked in vitro by incubation of CD4(+) peripheral blood lymphocytes with mycolactone. Our findings support the hypothesis that mycolactone contributes to bacterial persistence in human hosts by limiting the generation of adaptive cellular responses. Moreover, we identified immunological markers of BUD, which may be helpful for confirmatory diagnosis of the disease and, especially, for monitoring the response to antibiotic treatment.

Mycolactone impairs T cell homing by suppressing microRNA control of L-selectin expression

“…Mycolactone was known to block the capacity of primary T cells to produce multiple cytokines upon activation (2,6). Here, we show that mycolactone also impairs their migratory properties.…”

“…Mycolactone production is critical for bacterial virulence and underpins the pathogenesis of lesions marked by a striking lack of inflammatory infiltrates. The immune profiling of patients has recently revealed systemic defects in the production of multiple T-cell cytokines, suggesting that mycolactone impairs the generation of cellular responses (2). In line with this hypothesis, mycolactone was reported to suppress the production of various cytokines by monocytes, lymphocytes, and dendritic cells (DCs) in vitro (3)(4)(5)(6).…”

Suppressive effect of mycolactone-containing fraction from Mycobacterium ulcerans on antibody production against co-administered antigens

“…In addition, several in vitro studies have suggested that mycolactone could inhibit cytokine and chemokine production from immune cells such as T cells, macrophages, and dendritic cells [9][10][11][12][13]. These observations clearly suggested that mycolactone presents immunosuppressive effects and may have an important role in the successful infection of M. ulcerans in humans.…”

“…However, IgG 2a was not detected in any groups ( Figure 5). Phillips et al suggested that mycolactone inhibited the production of IL-4 and IFN-γ from human T cells [11]. The inhibitory effect of mycolactone on the cytokine production could be linked to the suppression of antibody production, given that IL-4 is an important cytokine that induces Th 2 -type immune response.…”

“…Injection of mycolactone into guinea pig produced an ulcer similar to Buruli ulcer [4]. Mycolactone inhibits the production of various cytokines, chemokines, and other secreted immune modulators [7] from immune cells such as monocytes [8], macrophages [9], dendritic cells [10], and T cells [11][12][13]. When a mycolactone-deficient strain of M. ulcerans was injected into model animals, a granuloma was successfully developed and the bacteria were cleared from the infected regions [14,15], suggesting that mycolactone has a suppressive effect on cell-mediated immune responses.…”