Mycolactone-Mediated Inhibition of Tumor Necrosis Factor Production by Macrophages Infected withMycobacterium ulceransHas Implications for the Control of Infection

Abstract

The pathogenicity of Mycobacterium ulcerans, the agent of Buruli ulcer, depends on the cytotoxic exotoxin mycolactone. Little is known about the immune response to this pathogen. Following the demonstration of an intracellular growth phase in the life cycle of M. ulcerans, we investigated the production of tumor necrosis factor (TNF) induced by intramacrophage bacilli of diverse toxigenesis/virulence, as well as the biological relevance of TNF during M. ulcerans experimental infections. Our data show that murine bone marrow-derived macrophages infected with mycolactone-negative strains of M. ulcerans (nonvirulent) produce high amounts of TNF, while macrophages infected with mycolactone-positive strains of intermediate or high virulence produce intermediate or low amounts of TNF, respectively. These results are in accordance with the finding that TNF receptor P55-deficient (TNF-P55 KO) mice are not more susceptible than wild-type mice to infection by the highly virulent strains but are more susceptible to nonvirulent and intermediately virulent strains, demonstrating that TNF is required to control the proliferation of these strains in animals experimentally infected by M. ulcerans. We also show that mycolactone produced by intramacrophage M. ulcerans bacilli inhibits, in a dose-dependent manner, but does not abrogate, the production of macrophage inflammatory protein 2, which is consistent with the persistent inflammatory responses observed in experimentally infected mice.

FVB/N Mice Spontaneously Heal Ulcerative Lesions Induced by Mycobacterium ulcerans and Switch M. ulcerans into a Low Mycolactone Producer

“…Buruli ulcer is a necrotizing skin infection, with skin lesions caused by mycolactone, the main virulence factor of M. ulcerans. This toxin is endowed with dermonecrotic (destruction of the skin and soft tissues) immunosuppressive activities and analgesic properties facilitating host colonization (3)(4)(5)(6)(7). In the absence of treatment, the lesions may evolve into massive ulcers and, in the most severe cases, bone is affected, leading to massive deformities.…”

IFN-γ–Dependent Activation of Macrophages during Experimental Infections by Mycobacterium ulcerans Is Impaired by the Toxin Mycolactone

“…Mycolactone was shown to passively diffuse through the plasmatic membrane of cells (18) inducing apoptosis and necrosis (4), having therefore an important impact on disease progression. This exotoxin induces cell death of the inflammatory infiltrate recruited during M. ulcerans infections (13,14,19) and inhibits the production of the macrophage-activating cytokine TNF (20,21). Nevertheless, in some individuals, a protective immune response is mounted, ultimately controlling the pathogen without clinical manifestations (22).…”

Punaises aquatiques et transmission deMycobacterium ulcerans

“…L'un des scénarios possible serait le suivant : au moins pendant les phases précoces dans le derme/hypoderme les bactéries seraient intracellulaires. Pendant la phase intracellulaire précoce avant que ne soit présente à des concentrations toxiques la mycolactone, la synthèse du facteur nécrosant des tumeurs TNF est inhibée mais celle de MIP-2 est induite, cette dernière chimiokine contribuant à l'initiation et au maintien des processus inflammatoires [6]. Ensuite, une partie de la population bactérienne devient extracellulaire dans des zones tissulaires nécrotiques et l'autre partie de la population est intracellulaire à la périphérie de la zone de nécrose.…”

“…Ainsi, le parasite serait une cible « innocente » de cette réaction immune qui n'est pas dirigée directement contre lui [9]. Le même mécanisme protecteur surviendrait chez l'homme, puisqu'une analyse sérologique mesurant les immunoglobulines G reconnaissant des constituants du suc salivaire des punaises, réalisée en zone endémique, a montré chez les patients présentant des lésions à M. ulcerans un taux d'IgG infé-rieur à celui de sujets exposés aux piqû-res des insectes mais sans lésion [6]. Ces observations rappellent l'immunité protectrice conférée par une exposition préalable aux protéines salivaires des tiques et des phlébotomes vecteurs des micro-organismes responsables de la leishmaniose ou de la maladie de Lyme.…”