Pathogenesis of Mycobacterium ulcerans infection

Mycobacterium ulcerans is the causative agent of Buruli Ulcer, a severe emerging infectious disease in West Africa. M. ulcerans produces large necrotic persistent skin infections which may result in the loss of affected limbs.  These ulcers are remarkable in that they are painless, and despite the large numbers of extracellular bacteria present, there is minimal acute inflammatory response to infection. In our laboratory we have isolated and characterized a polyketide-derived macrolide toxin (mycolactone) from M. ulcerans and shown that this toxin is responsible for the unique pathology of Buruli ulcer. We are currently investigating the immunomodulatory effects of mycolactone on human cells and in animal models. The goal of this research is to identify the cellular targets of mycolactone in order to understand the underlying mechanism of immunosuppression in Buruli Ulcer patients.  We are using DNA micro-array and proteomic approaches to gain information about host-bacterial interactions involved in M. ulcerans  disease.

Genetic analysis of mycolactone biosynthesis

Using genetic tools we have identified the mycolactone gene cluster in M. ulcerans and constructed mycolactone negative M. ulcerans. Genes for mycolactone biosynthesis are carried on a large plasmid within a 110kb gene cluster which includes 3 polyketide synthase genes and three accessory enzymes.  The virulence plasmid as well as the M. ulcerans chromosome has been recently sequenced by the Pasteur Institute, Paris.  We are presently developing genetic tools for analyzing mycolactone gene expression. We are interested in identifying regulatory pathways for mycolactone production as well in studying the kinetics of mycolactone in vivo.  We have recently discovered the mycolactone plasmid in M. liflandii, a frog pathogen and isolates of M. marinum from Israel.  Studies are underway to determine whether the mycolactone plasmid can be transferred by conjugation to new mycobacterial species.

Mycobacterium ulcerans as an environmental pathogen

M. ulcerans is an environmental pathogen which is contracted from environmental exposure and which does not spread from person to person.  In areas of high endemicity, 15% of the villagers may have Buruli ulcer and evidence suggests the infection is increasing in West Africa.  The only risk factor for infection is exposure to slow moving water.  The particular mode of transmission is unknown. Evidence suggests the presence of an environmental insect vector for M. ulcerans. In collaboration with the World Health Organization and Dr. Richard Merritt, at Michigan State University, we are conducting studies in Ghana in order to identify the source of M. ulcerans in the environment. In addition, we have established an insect infection model in the laboratory using insects collected in Ghana to provide evidence for the significance of insect colonization to disease in West Africa.

Buruli Ulcer Research

Professor Pam Small and her research group are part of a 7 country (Australia, Belgium, Switzerland, United States, Ghana, Benin, Cameroon) consortium which has been awarded a 1 million dollars per year for three years to conduct research on Buruli Ulcer. Professor  Small’s  share of this funding  is $301,000.  The research funds have been awarded by the Optimus Foundation. In addition, the McCord Research Foundation recently announced a $25,000 grant to be awarded to Professor Small for  studies on Buruli Ulcer.The title of her  part of this proposal is “Transmission of Buruli ulcer from the environment to humans.”