Project description:Mycolactone, a lipid-like toxin, is the major virulence factor of Mycobacterium ulcerans, the etiological agent of Buruli ulcer. Its involvement in lesions 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 showed 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 damages, 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 giving a new insight, thus paving the way for development of new therapeutic strategies, taking account the pro-inflammatory potential of mycolactone.
Project description:Buruli ulcer (BU) is a tropical infectious disease caused by Mycobacterium ulcerans. BU causes profound skin ulcerations and eventually bone infections. Life-long functional sequelae are observed in more than 20% of patients, most of whom are children. Several observations, in particular the large variability in the clinical severity of the disease after infection, suggested the role of human genetic factors in the development of BU. Here, we report two children with severe BU, born of consanguineous parents. The deep genetic exploration of this family led to the identification of a small deletion on chromosome 8 in both patients. The corresponding article is in press in PloS Neglected Tropical Diseases
Project description:Pressure ulcer (PU) is a chronic non-healing wound caused by continuous pressure of the bodyweight to the skin, which is often seen in spinal cord injury patients and in the bedridden elderly population. In spite of high mortality, the pathophysiology of PU remains poorly understood. We performed single-cell transcriptomic analysis of epidermal cells from PU wound-edges, and compared them with epidermal cells from the intact skin and normal acute wounds (AW) of healthy donors. We identified four keratinocyte clusters, one melanocyte cluster, and one immune cell cluster, and the cellular heterogeneity and gene expression were altered in PU. Our findings provided a high-resolution map of human PU and AW, which are likely to yield new areas for exploration of the pathophysiology of chronic wounds and development of wound therapy.
Project description:Marjolin’s Ulcer is an aggressive cutaneous malignancy that typically ensues over a period of time in the post-burned lesions and scars or any other chronic wound. Marjolin’s Ulcer makes up 1.2% of all skin cancers, it is reported that 2% of squamous cell carcinoma and 0.03% of basal cell carcinoma originate in burn scars. Recent studies have shown that long non-coding (lncRNA) plays critical roles in a myriad of biological processes and human diseases,Since the roles of lncRNA in Marjolin’s Ulcer remain unknown,they were investigated in the study.Our findings indicate that the expression profiles of lncRNAs has changed in Marjolin’s Ulcer as compared with normal skin and para-cancerous scar, and may provide novel insight into the molecular mechanism underlying the disease and potential novel diagnostic or therapeutic targets for Marjolin’s Ulcer.
Project description:Chronic, non-healing wounds contribute significantly to the suffering of patients with co-morbidities in the clinical population with mild to severely compromised immune systems. Normal wound healing proceeds through a well-described process. However, in chronic wounds this process seems to become dysregulated at the transition between resolution of inflammation and re-epithelialization. Bioburden in the form of colonizing bacteria is a major contributor to the delayed headlining in chronic wounds such as pressure ulcers. However how the microbiome influences the wound metabolic landscape is unknown. Here, we have used a Systems Biology approach to determine the association between the taxonomic and metabolomic profile of wounds colonized by bacteria. Pressure ulcer biopsies were harvested from primary chronic wounds and bisected into top and bottom sections prior to analysis of microbiome by pyrosequencing and analysis of metabolome using 1H nuclear magnetic resonance (NMR) spectroscopy. Bacterial taxonomy revealed that wounds were colonized predominantly by three main phyla, but differed significantly at the genus level. While taxonomic profiles demonstrated significant variability between wounds, metabolic profiles shared significant similarity based on the depth of the wound biopsy. Association between taxonomy and metabolic landscape indicated significant wound-to-wound similarity in metabolite enrichment sets and metabolic pathway impacts, especially with regard to amino acid metabolism. To our knowledge, this is the first demonstration of a statistically robust correlation between bacterial colonization and metabolic landscape within the chronic wound environment.