Abstract
Mycolactone, a lipid-like toxin, is the major virulence factor of Mycobacterium ulcerans, the etiological agent of Buruli ulcer. Its involvement in lesion development has been widely described in early stages of the disease, through its cytotoxic and immunosuppressive activities, but less is known about later stages. Here, we revisit the role of mycolactone in disease outcome and provide the first demonstration of the pro-inflammatory potential of this toxin. We found that the mycolactone-containing mycobacterial extracellular vesicles produced by M. ulcerans induced the production of IL-1β, a potent pro-inflammatory cytokine, in a TLR2-dependent manner, targeting NLRP3/1 inflammasomes. We show our data to be relevant in a physiological context. The in vivo injection of these mycolactone-containing vesicles induced a strong local inflammatory response and tissue damage, which were prevented by corticosteroids. Finally, several soluble pro-inflammatory factors, including IL-1β, were detected in infected tissues from mice and Buruli ulcer patients. Our results revisit Buruli ulcer pathophysiology by providing new insight, thus paving the way for the development of new therapeutic strategies taking the pro-inflammatory potential of mycolactone into account.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Animals
-
Buruli Ulcer / immunology*
-
Buruli Ulcer / metabolism
-
Buruli Ulcer / pathology
-
Extracellular Vesicles / metabolism
-
Humans
-
Inflammation / immunology*
-
Inflammation / metabolism
-
Inflammation / microbiology
-
Interleukin-1beta / immunology*
-
Interleukin-1beta / metabolism
-
Macrolides / immunology*
-
Macrolides / metabolism
-
Macrolides / toxicity
-
Mice
-
Mice, Inbred C57BL
-
Mycobacterium ulcerans
Substances
-
Interleukin-1beta
-
Macrolides
-
mycolactone
Grants and funding
This work was supported by INSERM, Fondation Raoul Follereau France, Agence Nationale de la Recherche: BU_SPONT_HEAL project (InfectEra, grant no. ANR-15-IFEC-0006) and MYCOPARADOX ANR project (grant no. ANR-16-CE12-0023), the Pays de la Loire region (STARTER), and Fondation pour la Recherche Médicale (Equipe FRM, grant no. R20104NN). J.M., L.A., and A.A. received support from the Laboratoire d’Excellence Integrative Biology of Emerging Infectious Diseases (grant no. ANR-10-LABX-62-IBEID) and the ANR under the “Investments for the Future” program (grant no. ANR-10-IAHU-01). Y.B. received a salary from STARTER Project, L.E. from Foundation Raoul Follereau. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.