Buruli Ulcer, Susceptibility To

A number sign (#) is used with this entry because of evidence that susceptibility to Buruli ulcer is associated with variation in the NRAMP1 gene (SLC11A1; 600266) on chromosome 2q35.

Description

Buruli ulcer is an infectious disease prevalent in many tropical and subtropical regions caused by infection with Mycobacterium ulcerans. It is the third most frequent mycobacterial disease in humans worldwide, after tuberculosis (607948) and leprosy (246300). Lesions are most common on exposed parts of the body, especially the limbs. Buruli ulcer derives its name from a county in Uganda, East Africa, north of Kampala, where the disease was found in the late 1950s in hundreds of people living near marshes and riverine areas near the Nile River (Clancey et al., 1961; Barker, 1971). The disease was first described in the medical literature in 1948 in a report on patients in Australia (MacCallum et al., 1948). Patients have also been reported from tropical areas in Latin America and Asia (Stienstra et al., 2006; van der Werf et al., 2005).

Clinical Features

The preulcerative stage of Buruli ulcer includes nodules, plaques, or edema. Ulcerative lesions have undermined edges induced by secretion of the unique mycobacterial toxin, mycolactone, which destroys fat cells. Later, a granulomatous healing response occurs that may lead to severe and permanent functional limitations (Stienstra et al., 2006). For a review, see van der Werf et al. (2005).

Pathogenesis

M. ulcerans produces mycolactone, a macrolide toxin essential for bacterial virulence and necrotic skin ulcers characterized by a lack of inflammation. Using a variety of techniques, Guenin-Mace et al. (2013) showed that mycolactone bound selectively and significantly to the GTPase-binding domains of WASP (300392) and NWASP (605056) in a dose-dependent manner. Mycolactone induced stimulation of NWASP-mediated mediated actin polymerization independent of CDC42 (116952). Mycolactone also promoted perinuclear recruitment and activation of ARP2/3 (see 604221) by NWASP in both anchorage-dependent and -independent cell lines. Confocal microscopy demonstrated that defective adhesion, associated with impaired membrane localization of cadherin (see CDH1; 192090), resulted from mycolactone-induced NWASP activation. A wound-healing assay showed that directionality was impaired in cells exposed to mycolactone. Injection of mycolactone into mouse ears caused progressive thinning of the external stratum granulosum and lucidum and reduced epidermis width in association with a dramatic loss of E-cadherin-adhesive contacts in the stratum spinosum. Coadministration of an NWASP inhibitor, wiskostatin, suppressed epidermal thinning. Guenin-Mace et al. (2013) proposed that modulation of mycolactone-induced NWASP activation might counteract the ulcerative effect of the toxin in the treatment of Buruli ulcer.

Marion et al. (2014) noted that the skin lesions caused by M. ulcerans are not accompanied by pain, despite their severity. They infected mouse footpads with M. ulcerans or injected them with the mycolactone toxin produced by the bacteria and found that the resulting redness and edema were painless, as assessed by an adaptation of the pain-receptive tail-flick assay. Histologic analysis demonstrated that the painlessness was not due to nerve degeneration, as was previously thought, and was attributable to the mycolactone toxin. Patch-clamp analysis showed that mycolactone induced neuron hyperpolarization involving potassium efflux through Traak (KCNK4; 605720). Targeting of 8,000 genes by small interfering RNA implicated At2r (AGTR2; 300034) as a nociceptive pathway receptor that could account for the analgesic effect of mycolactone. Neurons from At2r-null mice were not hyperpolarized in response to mycolactone via the cyclooxygenase pathway, and footpads from At2r-null mice exhibited unaltered pain sensitivity following mycolactone injection. RT-PCR analysis revealed that expression of At2r in mouse footpad was not upregulated following M. ulcerans infection. Binding assays showed that mycolactone inhibited binding of an agonist to human AT2R. Although mycolactone also bound to human AT1R (AGTR1; 106165), it did not induce hyperpolarization via AT1R in human cells and mouse neurons. Marion et al. (2014) concluded that AT2R plays a pivotal role in the signaling cascade of mycolactone-induced hypoesthesia following M. ulcerans infection.

By competitive binding analyses, Baron et al. (2016) showed that mycolactone bound tightly to SEC61A (SEC61A1; 609213) and had a slow dissociation rate. Screening of SEC61A mutants expressed in embryonic kidney cells revealed that mutations at arg66 or ser82 conferred resistance to cytotoxicity and mycolactone-mediated blockade of protein secretion and translocation. These mutations are located near the luminal plug of SEC61A. Proteomic analysis and in vitro translation experiments showed that a broad spectrum of proteins, particularly secreted proteins (e.g., IFNG; 147570) and single-pass type I/II membrane proteins (e.g., TNF; 191160), as well as the ER-resident protein BIP (HSPA5; 138120), were affected by mycolactone inhibition of SEC61A. Mycolactone inhibition of wildtype, but not mutant, Sec61 activity prevented production of Ifng by mouse T cells and responsiveness to Ifng through Ifngr (107470) in mouse macrophages. Mycolactone also affected Sec61-dependent Cd62l (153240) expression and Cd62l-dependent lymphocyte homing in mice. Baron et al. (2016) concluded that mycolactone inhibition of SEC61 prevents the production of key mediators of innate and adaptive immune responses against intracellular pathogens.

Clinical Management

Although antibiotic regimens may have some success against Buruli ulcer, surgery remains the mainstay of treatment. If treated early, amputation or scarring and permanent functional limitations can be avoided. For a review, see van der Werf et al. (2005).

Molecular Genetics

Stienstra et al. (2006) hypothesized that many individuals exposed to Mycobacterium ulcerans never develop Buruli ulcer disease. Since polymorphisms in NRAMP1 are associated with both tuberculosis and leprosy, they conducted a cross-sectional analysis of 182 Buruli ulcer patients in Ghana and 191 healthy neighborhood-matched controls for 3 NRAMP1 polymorphisms. A statistically significant association was found for a G-to-A SNP in exon 15 that leads to a nonconservative asp543-to-asn substitution (D543N; 600266.0002). A similar association with D543N had been found in tuberculosis patients in the Gambia (Bellamy et al., 1998). No Ghanaians were homozygous for the A allele of this SNP. Stienstra et al. (2006) determined that the population attributable risk of D543N is 13%, and they proposed that other genes are likely to be involved in Buruli ulcer susceptibility.