Abstract
BackgroundThe neglected tropical disease Buruli ulcer (BU) caused by Mycobacterium ulcerans is an infection of the subcutaneous tissue leading to chronic ulcerative skin lesions. Histopathological features are progressive tissue necrosis, extracellular clusters of acid fast bacilli (AFB) and poor inflammatory responses at the site of infection. After the recommended eight weeks standard treatment with rifampicin and streptomycin, a reversal of the local immunosuppression caused by the macrolide toxin mycolactone of M. ulcerans is observed.Methodology/Principal FindingsWe have conducted a detailed histopathological and immunohistochemical analysis of tissue specimens from two patients developing multiple new skin lesions 12 to 409 days after completion of antibiotic treatment. Lesions exhibited characteristic histopathological hallmarks of Buruli ulcer and AFB with degenerated appearance were found in several of them. However, other than in active disease, lesions contained massive leukocyte infiltrates including large B-cell clusters, as typically found in cured lesions.Conclusion/SignificanceOur histopathological findings demonstrate that the skin lesions emerging several months after completion of antibiotic treatment were associated with M. ulcerans infection. During antibiotic therapy of Buruli ulcer development of new skin lesions may be caused by immune response-mediated paradoxical reactions. These seem to be triggered by mycobacterial antigens and immunostimulators released from clinically unrecognized bacterial foci. However, in particular the lesions that appeared more than one year after completion of antibiotic treatment may have been associated with new infection foci resolved by immune responses primed by the successful treatment of the initial lesion.
Highlights
Buruli ulcer (BU) is a chronic necrotizing infection of subcutaneous tissue caused by Mycobacterium ulcerans [1,2,3,4]
M. ulcerans produces a toxin with a polyketide-derived macrolide structure, named mycolactone, which plays a central role in tissue destruction and local immunosuppression
Buruli ulcer (BU) is a chronic necrotizing skin disease presenting with extensive tissue destruction and local immunosuppression
Summary
Buruli ulcer (BU) is a chronic necrotizing infection of subcutaneous tissue caused by Mycobacterium ulcerans [1,2,3,4]. After destruction of subcutaneous tissue, the skin may break down centrally leading to the development of largely painless necrotic skin ulcers with characteristic undermined edges. These may progress to large necrotic lesions. M. ulcerans produces a toxin with a polyketide-derived macrolide structure, named mycolactone, which plays a central role in tissue destruction and local immunosuppression. Observations both in cell culture and infection models indicate that cells infiltrating BU lesions are killed due to the cytotoxic and apoptosis inducing activity of mycolactone [7,8,9,10]. After the recommended eight weeks standard treatment with rifampicin and streptomycin, a reversal of the local immunosuppression caused by the macrolide toxin mycolactone of M. ulcerans is observed
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