Susceptibility to development of Mycobacterium ulcerans disease: review of possible risk factors

Abstract

SummaryMycobacterium ulcerans disease, also known as Buruli ulcer (BU), is a disease of subcutaneous fat tissue. BU is prevalent in riverine and swamp areas of the tropical zone in Africa, Asia and South America, and a few scattered foci in Australia. The mode of transmission of M. ulcerans has not been fully elucidated, but inoculation into the subcutaneous tissues probably occurs through penetrating skin trauma. BU has not been linked with HIV infection. Antimycobacterial drug treatment is ineffective, and treatment is surgical. Patients eventually develop scars and contractures, with resulting disabilities, and the disease imposes a large burden on affected populations. The incidence of BU has dramatically increased in West African countries over the last decade. There is an urgent need for research into host and environmental risk factors for BU in order to develop effective strategies to combat this disease. We review possible genetic host susceptibility factors for BU that are relevant in other mycobacterial diseases: natural resistance-associated macrophage protein-1 (NRAMP-1), HLA-DR, vitamin D 3 receptor, mannose binding protein, interferon-gamma (IFN-c) receptor, tumour necrosis factor alpha (TNF-a), interleukin (IL)-1a, 1b and their receptor antagonists; and IL-12. Schistosoma haematobium infection is highly endemic in many BU foci in West Africa, with a striking increase in transmission after river dams were constructed. This observation, and the observations from interaction of schistosomiasis and tuberculosis, have fuelled our hypothesis that schistosomiasis is a risk factor for BU by driving the host immune response towards a predominantly Th-2 pattern, away from a Th-1 preponderant protection against mycobacterial infection. If the latter hypothesis is con®rmed, enhanced schistosomiasis control should impact on BU.

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

“…On the other hand, in a more recent study, Phillips et al (27), using a higher number of patients, reported a strong expression of IFN-g in both nodular and ulcerative lesions. Also in line with our findings, supporting therefore the existence of protective cellular-mediated immune and delayed-type hypersensitivity responses, associated with IFN-g production in the context of Th1 responses, when BU disease progresses to healing, granuloma formation occurs (3,46,(53)(54)(55), and the positivity of the Burulin skin test increases (56)(57)(58). In addition, BCG vaccination was found to protect humans against BU osteomyelitis (59), and BCG or a DNA vaccine encoding Ag85A from BCG confer some degree of protection against M. ulcerans experimental infections (60,61).…”

The local immune response in ulcerative lesions of Buruli disease

“…In the ulcerative non-granulomatous lesions it was common that bacteria were overlying cells, but in some peripheral areas distant to necrosis we found fewer and dispersed bacilli; in these areas some macrophages showed well-defined intracellular AFB, suggesting real phagocytosed mycobacteria. This observation is in agreement with recent in vitro studies which demonstrated that occasional macrophages can be infected by M. ulcerans [23], and with the concept that M. ulcerans has an intracellular phase that is necessary for the induction of a Th1 immune response [24,25]. It has been demonstrated recently that mycolactone is anti-phagocytic, but macrophages can phagocytose M. ulcerans during early experimental infection and transport the bacilli to the regional lymph nodes [26].…”

Infection withMycobacterium ulceransInduces Persistent Inflammatory Responses in Mice

“…As shown, in progressive murine infection by virulent M. ulcerans, such a switch is not fully completed. This observation correlates with the finding that progressive infection of the skin, disseminated disease, and osteomyelitis in BU patients were associated with an absence of granulomas in the infected areas (33,49,66). Conversely, with the noncytotoxic strain 5114, which is not virulent for mice and does not cause leukocyte death and necrosis of the subcutaneous tissue at any stage of infection, the acute neutrophilic profile of the cellular infiltrate gradually switches to a predominance of mononuclear cells and formation of granuloma-like structures.…”

“…Conversely, with the noncytotoxic strain 5114, which is not virulent for mice and does not cause leukocyte death and necrosis of the subcutaneous tissue at any stage of infection, the acute neutrophilic profile of the cellular infiltrate gradually switches to a predominance of mononuclear cells and formation of granuloma-like structures. Not surprisingly, this type of chronic response was observed in BU patients during the healing phase of disease (30,31,40,49,66,74).…”