Université d'Angers, INSERM, CRCINA, Angers, France.
Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM, Paris, France.
PLoS Pathog. 2020 Dec 18;16(12):e1009107. doi: 10.1371/journal.ppat.1009107. eCollection 2020 Dec.
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.
Mycolactone 是一种类脂毒素，是导致溃疡分枝杆菌（引起 Buruli 溃疡的病原体）产生的主要毒力因子。其细胞毒性和免疫抑制活性已在疾病早期的发病机制中得到广泛描述，但对疾病后期的作用知之甚少。在这里，我们重新审视了 mycolactone 在疾病结局中的作用，并首次证明了这种毒素的促炎潜力。我们发现，溃疡分枝杆菌产生的含有 mycolactone 的胞外囊泡以 TLR2 依赖的方式诱导产生白细胞介素 1β（一种强效促炎细胞因子），靶向 NLRP3/1 炎性小体。我们的数据在生理环境下是相关的。这些含有 mycolactone 的囊泡在体内注射后会引起强烈的局部炎症反应和组织损伤，皮质类固醇可以预防这种损伤。最后，在感染组织中检测到几种可溶性促炎因子，包括白细胞介素 1β，这些因子也存在于小鼠和 Buruli 溃疡患者的感染组织中。我们的结果通过提供新的见解重新审视了 Buruli 溃疡的病理生理学，为考虑 mycolactone 的促炎潜力开发新的治疗策略铺平了道路。
