Abstract
BackgroundBuruli ulcer (BU) is a neglected necrotizing disease of the skin, subcutaneous tissue and bone, caused by Mycobacterium ulcerans. BU pathogenesis is associated with mycolactone, a lipidic exotoxin with cytotoxic and immunosuppressive properties. Since 2004, the World Health Organization recommends the treatment of BU with a combination of rifampicin and streptomycin (RS). Histological analysis of human tissue samples suggests that such antibiotic treatment reverses the mycolactone-induced local immunosuppression, leading to increased inflammatory infiltrations and phagocytosis of bacilli.Methodology/Principal FindingsWe used a mouse model of M. ulcerans footpad infection, followed by combined RS treatment. Time-lapsed analyses of macroscopic lesions, bacterial burdens, histology and immunohistochemistry were performed in footpads. We also performed CFU counts, histology and immunohistochemistry in the popliteal draining lymph nodes (DLN). We observed a shift in the cellular infiltrates from a predominantly neutrophilic/macrophagic to a lymphocytic/macrophagic profile in the infected footpads of antibiotic-treated mice. This shift occurred before the elimination of viable M. ulcerans organisms, which were ultimately eradicated as demonstrated by the administration of dexamethasone. This reduction of bacillary loads was accompanied by an increased expression of inducible nitric oxide synthase (NOS2 or iNOS). Predominantly mononuclear infiltrates persisted in the footpads during and after treatment, coincident with the long persistence of non-viable poorly stained acid-fast bacilli (AFB). We additionally observed that antibiotherapy prevented DLN destruction and lymphocyte depletion, which occurs during untreated experimental infections.Conclusions/SignificanceEarly RS treatment of M. ulcerans mouse footpad infections results in the rapid elimination of viable bacilli with pathogen eradication. However, non-viable AFB persisted for several months after lesion sterilization. This RS regimen prevented DLN destruction, allowing the rapid re-establishment of local and regional cell mediated immune responses associated with macrophage activation. Therefore it is likely that this re-establishment of protective cellular immunity synergizes with antibiotherapy.
Highlights
Buruli ulcer (BU), caused by the environmental pathogen Mycobacterium ulcerans, is a necrotizing disease of the skin, subcutaneous tissue and bone
Since the recommendation by World Health Organization (WHO) in 2004 of treating BU patients with a regimen of antibiotherapy combining rifampicin and streptomycin (RS), clinical studies gave rise to the hypothesis that a synergistic effect between antibiotics and the host immune system is in place to clear M. ulcerans infection [18,22,23]
RS are bactericidal against extracellular and intramacrophage susceptible mycobacteria [41] and the quick reduction in M. ulcerans colony forming units (CFU) counts in treated mice ([14,42,43] and present results) suggests that such mode of antimycobacterial activity operates in vivo
Summary
Buruli ulcer (BU), caused by the environmental pathogen Mycobacterium ulcerans, is a necrotizing disease of the skin, subcutaneous tissue and bone. This disease is the third most common mycobacterial infection in the world, after tuberculosis and leprosy. Since 2004, the World Health Organization (WHO) recommends a combination of the antibiotics rifampicin and streptomycin (RS) for the treatment of BU [11] This recommendation was based on the successful results obtained in a small clinical trial carried on from 2001 to 2002 in Ghana with patients with early nonulcerative lesions [12], and following promising studies showing bacterial killing in M. ulcerans–infected mice treated with rifampicin and an aminoglycoside (amikacin or streptomycin) [13,14,15]. Buruli ulcer (BU) is a neglected necrotizing disease of the skin, subcutaneous tissue and bone, caused by Mycobacterium ulcerans. Histological analysis of human tissue samples suggests that such antibiotic treatment reverses the mycolactone-induced local immunosuppression, leading to increased inflammatory infiltrations and phagocytosis of bacilli
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