Royal Society Africa Prize Seminar 2018

Buruli ulcer (BU) is a neglected tropical skin disease caused by Mycobacterium ulcerans. BU cases have been reported from more than 30 countries, but the major burden of the disease lies on children in remote rural areas of Central and West Africa. M. ulcerans produces a unique cytotoxic macrolide exotoxin designated mycolactone that is responsible for the chronic necrotising nature of the disease. Since the exact mode of transmission of M. ulcerans is still not entirely understood, early diagnosis and treatment are cornerstones of current BU control strategies.

Since BU patients present with diverse clinical manifestations, differential diagnosis is manifold and clinical misclassification occurs frequently. Therefore we are aiming for the development of antigen capture assays that can be converted into rapid diagnostic tests suitable for point-of-care use. Traditionally surgical excision of M. ulcerans affected tissue was the standard therapy for BU till the World Health Organization published in 2004 provisional guidelines recommending an eight week combination therapy with streptomycin and rifampicin. To develop alternative treatment modalities that are shorter and associated with less severe side effects, we are testing new scaffolds with anti-M. tuberculosis activity against M. ulcerans and are optimising local thermotherapy against the thermosensitive M. ulcerans bacteria. Furthermore, we are evaluating mycolactone as vaccine target and found that mycolactone specific antibodies have toxin neutralising activity.

Tuberculosis (TB) and Buruli ulcer (BU) caused by Mycobacterium ulcerans (Mu) are two of the three main mycobacterial diseases. While TB is globally distributed BU is restricted mainly to West and central Africa. Nevertheless, tuberculosis caused by M africanum (Maf) is restricted to West-Africa and like Mu has been neglected and not much studied. In Dr Dorothy Yeboah-Manu’s lab, the group has undertaken innovative studies to provide evidence for revising some of the long-held notions that have mitigated against the effective control of these diseases. Using a multidisciplinary approach, they have provided evidence towards understanding and improvement of diagnosis, treatment, epidemiology and transmission (four of the six WHO research priority areas) of BU. For example, the group showed that African isolates were genetically distinct, water may not be actively involved in the transmission of Mu and the T cell anergy observed in BU is not permanent but is related to the presence of viable Mu. Dorothy’s work in TB has largely been towards the understanding of the biology of Maf. In two independent studies, the group showed that Maf might have adapted to a specific ethnic group, and also found a reduced transmission of Maf, albeit persistently present in Ghana. Their comparative genomics analysis of Maf and Mtb isolates found these pathogens are genomically distinct with lineage-specific genomic erosions, mutations and conservation of human T cell antigens and epitopes. Dorothy will use funds from this award and other grants to expand the group studies to understand the phenotypic implications of the observed genomic variations.

We still have much to learn about mycobacteria, and how the human host responds to mycobacterial infection. We know that macrophages and T cells are critically important in immunity to Mycobacterium tuberculosis, but although T cell activation or production of IFNg can be used to assess the immunogenicity of candidate TB vaccines, they have not given us confirmed correlates of protection. Analysis of host gene expression can provide new insights into the pathogenesis of tuberculosis, the success or failure of chemotherapy, and early diagnosis of disease. Another approach is to evaluate how immunity and host gene expression are modulated by environment, co-infection, and co-morbidity. Many more large-scale studies are required along with better comparative studies of infections caused by mycobacteria other than M. tuberculosis, such as M. ulcerans, M. leprae and M. africanum. Finally we need to integrate studies on the mycobacteria themselves with those of the host immune responses that they induce. Although we do not yet have a new effective vaccine to protect us against tuberculosis, these approaches have the potential to deliver both new insights and field-friendly point of care tests.