Abstract
Buruli ulcer (BU) is a chronic necrotizing disease of the skin and subcutaneous fat tissue. The causative agent, Mycobacterium ulcerans, produces mycolactone, a macrolide toxin, which causes apoptosis of mammalian cells. Only a small proportion of individuals exposed to M. ulcerans develop clinical disease, as surrounding macrophages may control the infection by bacterial killing at an early stage, while mycolactone concentration is still low. Otherwise, bacterial multiplication leads to in higher concentrations of mycolactone, with formation of necrotizing lesions that are no more accessible to immune cells. By typing a cohort of 96 Ghanaian BU patients and 384 endemic controls without BU, we show an association between BU and single nucleotide polymorphisms (SNPs) in iNOS (rs9282799) and IFNG (rs2069705). Both polymorphisms influence promoter activity in vitro. A previously reported SNP in SLC11A1 (NRAMP, rs17235409) tended to be associated with BU. Altogether, these data reflect the importance of IFNG signaling in early defense against M. ulcerans infection.
Highlights
Buruli ulcer (BU) is a necrotizing skin disease caused by Mycobacterium ulcerans, a slow growing mycobacterium, which can result in permanent functional disabilities (Junghanss et al, 2014)
IFNG activation increases the capacity of macrophages to kill intracellular mycobacteria by enhancing antimicrobial effector pathways, including iNOS, phagosomal maturation and autophagy, all of which play critical roles in the clearance of mycobacteria (Nunes-Alves et al, 2014)
IFNG knockout mice were found to be more susceptible than wild type mice in a footpad model of M. ulcerans infection (Bieri et al, 2016)
Summary
Buruli ulcer (BU) is a necrotizing skin disease caused by Mycobacterium ulcerans, a slow growing mycobacterium, which can result in permanent functional disabilities (Junghanss et al, 2014). Mycolactone suppresses dendritic cell (DC) maturation and reduces their ability to respond to stimulation, secondarily affecting T-cell activation (Pahlevan et al, 1999; Coutanceau et al, 2007; Boulkroun et al, 2010) Despite these immunosuppressive activities of mycolactone there is evidence that many exposed individuals do not develop clinical disease (Diaz et al, 2006; Yeboah-Manu et al, 2012; Roltgen et al, 2014). In a M. ulcerans mouse footpad infection model it was found that IFNG knockout mice display a faster disease progression compared to wild type mice (Bieri et al, 2016) This accelerated progression was reflected by faster and more extensive tissue necrosis, as well as by a significantly higher bacterial burden. We conducted a case-control candidate gene study to identify polymorphisms affecting susceptibility to BU
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