Mycobacterium ulcerans challenge strain selection for a Buruli ulcer controlled human infection model.

Critical scientific questions remain regarding infection with Mycobacterium ulcerans, the organism responsible for the neglected tropical disease, Buruli ulcer (BU). A controlled human infection model has the potential to accelerate our knowledge of the immunological correlates of disease, to test prophylactic interventions and novel therapeutics. Here we present microbiological evidence supporting M. ulcerans JKD8049 as a suitable human challenge strain. This non-genetically modified Australian isolate is susceptible to clinically relevant antibiotics, can be cultured in animal-free and surfactant-free media, can be enumerated for precise dosing, and has stable viability following cryopreservation. Infectious challenge of humans with JKD8049 is anticipated to imitate natural infection, as M. ulcerans JKD8049 is genetically stable following in vitro passage and produces the key virulence factor, mycolactone. Also reported are considerations for the manufacture, storage, and administration of M. ulcerans JKD8049 for controlled human infection.

A Mycobacterium ulcerans vaccine pilot trial using an accurate low-dose challenge.

A Mycobacterium ulcerans human challenge model has the potential to fundamentally advance our understanding of early human immune responses to infection, while rapidly evaluating vaccines and other therapeutic interventions. Here, using a murine tail infection model, we tested a very well-characterized working cell bank of the proposed challenge isolate M. ulcerans JKD8049 in naïve and Mycobacterium bovis bacille Calmette-Guérin (BCG)-vaccinated BALB/c mice. All 10 naïve mice were successfully infected with 20 colony-forming units (CFU) of M. ulcerans [95% confidence interval (CI) 17-22 CFU] with a mean time to visible lesion of 86 days (95% CI 79-92 days). In the 10 vaccinated mice, there was a significant delay in the mean time to lesion compared to the naïve controls of 24 days (P = 0.0003), but all mice eventually developed ulcerative lesions. This study informs a future human infection model by demonstrating the successful application of the challenge agent in this in vivo model and highlights both the promise and the problems with trying to induce protective immunity against M. ulcerans. IMPORTANCE: In preparation for its proposed use in a controlled human infection model (CHIM), this study reports the successful infection of BALB/c mice using a carefully characterized, low-dose inoculum of Mycobacterium ulcerans JKD8049 (our proposed CHIM strain). We also demonstrate that Mycobacterium bovis bacille Calmette-Guérin delays the onset of disease but cannot alter the course of illness once a lesion becomes apparent. We also validate the findings of previous low-dose challenges that used less accurate methods to determine the inoculum, but our presented methodology is practical, accurate, and anticipated to be reproducible.

Úlcera de Buruli / Buruli ulcer

A úlcera de Buruli, uma doença infecciosa causada pela Mycobacterium ulcerans (M. ulcerans),é a terceira micobacteriose em ocorrência, após a hanseníase e a tuberculose. Essa micobacteriose atípica tem sido relatada em mais de 30 países, principalmente, nos que têm climas tropicais e subtropicais, mas a sua epidemiologia permanece obscura. Recentemente, os primeiros casos autóctones do Brasil foram relatados, fazendo com que dermatologistas brasileiros estejam atentos a esse diagnóstico. O quadro clínico varia: nódulos, áreas de edema, placas, mas a manifestação mais típica é uma grande úlcera, que ocorre, em geral, nas pernas ou nos braços. Apesar do amplo conhecimento quanto ao seu quadro clínico em países endêmicos, nas outras áreas, esse diagnóstico pode passar despercebido. Assim, médicos devem ser orientados quanto à úlcera de Buruli, pois o diagnóstico precoce, o tratamento específico e a introdução de cuidados na prevenção de incapacidades são essenciais para uma boa evolução.

Buruli ulcer, an infectious disease caused by Mycobacterium ulcerans, is the third most prevalent mycobacteriosis, after tuberculosis and leprosy. This atypical mycobacteriosis has been reported in over 30 countries, mainly those with tropical and subtropical climates, but its epidemiology remains unclear. The first autochthonous cases of infection in Brazil have recently been described, making this diagnosis important for Brazilian dermatologists. Clinical manifestations vary from nodules, areas of edema, and plaques, but the most typical presentation is a large ulcer, usually in the limbs. Despite considerable knowledge about its clinical manifestations in some endemic countries, in other areas the diagnosis may be overlooked. Therefore, physicians should be educated about Buruli ulcer, since early diagnosis and treatment, including measures to prevent disability, are essential for a good outcome.