Elucidating the role of bacterial toxin-containing extracellular vesicles in Buruli ulcer onset – myEVs
Buruli ulcer disease (BUD) is a neglected tropical illness and the third most common mycobacterial disease, after tuberculosis and leprosy. This debilitating and progressive skin disease is caused by Mycobacterium ulcerans (M. ulcerans). BUD is a necrotizing hypodermitis that has received little attention. The limited tools to combat BUD underscore the importance of developing better therapeutic approaches to accelerate wound healing, as recommended by WHO. The main M. ulcerans virulence factor is mycolactone, a lipid toxin, synthesized by polyketide synthases. The ability of bacilli to escape the immune system is attributed to the immunosuppressive and cytotoxic effect of mycolactone. But, in some studies, it is suggested that the cell infiltrate from the belt actively secretes mediators of inflammation or that the susceptibility to BUD involved autophagy pathways. To uncover in vivo mechanisms underlying the development of BUD, we propose an experimental strategy built on the following critical observations: (i) our observations indicate that the cellular infiltrate at the site of infection is not inactivated during lesion progression in both human lesions and mouse model; (ii) we recently demonstrated that mycolactone-containing M. ulcerans extracellular vesicles confers this toxin the ability to activate pro-inflammatory responses both in vivo and in vitro; (iii) we identified an animal model that faithfully recapitulates this central feature of BUD in humans, including spontaneous healing. This experimental tool will provide a convenient approach to investigate critical mechanistic aspects of BUD in vivo. We propose to elucidate the role of mycolactone in BUD by revisiting the broadly-accepted view that mycolactone is strictly an anti-inflammatory and cytotoxic toxin. Therefore, the main objective will be to uncover and characterize potential cellular responses triggered by M. ulcerans mycolactone-containing vesicles during lesion progression.
Madame Estelle Marion (Institut national de la sante et de la recherche medicale)
The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.
LISM Centre national de la recherche scientifique
INCIT Institut national de la sante et de la recherche medicale
Help of the ANR 331,994 euros
Beginning and duration of the scientific project: September 2022 - 48 Months