Mycobacterium ulcerans, the cause of Buruli ulcer, is an environmental mycobacterium with a distinct geographic distribution. The reasons why only some individuals who are exposed to M. ulcerans develop ulcers are not known but are likely to reflect individual differences in the immune response to infections with this bacterium. In this study, we investigated cytokine profiles of peripheral blood mononuclear cells (PBMC) from 23 Buruli ulcer patients and 25 household contacts in a region of Australia where Buruli ulcer is endemic. The results showed that following stimulation with M. ulcerans or Mycobacterium bovis BCG, PBMC from Buruli ulcer patients mounted a Th2-type response, which was manifested by the production of mRNA for interleukin 4 (IL-4), IL-5, IL-6, and IL-10, whereas unaffected contacts responded mainly with the Th1 cytokines gamma interferon (IFN-␥) and IL-12. For example, mRNA for IL-4 was detected in 18 of 23 patients but in only 3 of 25 control subjects (P < 0.0001). By contrast, PBMC from 21 of 25 unaffected individuals produced IFN-␥ compared with 3 of 23 patients (P < 0.0001). IFN-␥ release following stimulation with mycobacteria was markedly reduced in affected subjects. Frequencies of antibodies to M. ulcerans in serum samples from affected and unaffected subjects were similar, indicating that many of the control subjects had been exposed to this bacterium. Together, these findings suggest that a Th1-type immune response to M. ulcerans may prevent the development of Buruli ulcer in people exposed to M. ulcerans, but a Th-2 response does not.

Mycobacterium ulcerans is a slow-growing, acid-fast bacillus that causes chronic necrotizing skin ulcers known as Buruli ulcers. Previously reported information on immunity to this mycobacterium is limited. We examined immune responses to M. ulcerans and M. bovis BCG in patients with M. ulcerans disease and in 20 healthy control subjects (10 tuberculin test positive and 10 tuberculin test negative). Cell-mediated immunity was assessed by stimulating peripheral blood mononuclear cells (PBMC) with whole mycobacteria and then measuring PBMC proliferation and the production of gamma interferon (IFN-␥). Humoral immunity was assessed by immunoblotting. PBMC from all subjects showed significantly greater proliferation and IFN-␥ production in response to stimulation with living mycobacteria compared with killed cells. However, PBMC from subjects with past or current M. ulcerans disease showed significantly reduced proliferation and production of IFN-␥ in response to stimulation with live M. ulcerans or M. bovis than PBMC from healthy, tuberculin test-positive subjects (P < 0.001) and showed results in these assays comparable to those of tuberculin testnegative subjects (P > 0.2). Serum from 9 of 11 patients with M. ulcerans disease, but no control subject, contained antibodies to M. ulcerans. The results indicate that patients with M. ulcerans infection mount an immune response to M. ulcerans as evidenced by antibody production, but they demonstrate profound systemic T-cell anergy to mycobacterial antigens. These findings may explain some of the distinct clinical and pathological features of M. ulcerans-induced disease.Mycobacterium ulcerans is the third most frequent cause of mycobacterial infections in immunocompetent individuals, after M. tuberculosis and M. leprae (18). M. ulcerans-induced disease generally manifests itself as indolent cutaneous ulcers, known as Buruli ulcers, accompanied by minimal systemic symptoms. Unlike other mycobacterial diseases, infections with M. ulcerans are characterized by extracellular bacteria, a lack of inflammatory cells, and extensive tissue necrosis at the site of infection (18). The indolent course, prominent extracellular bacteria, paucity of mononuclear cell infiltrate, and lack of systemic symptoms suggest a depressed or absent T-cell immune response.There are no published studies on the in vitro immune response of subjects with M. ulcerans infection. Although some individuals demonstrate a delayed-type hypersensitivity response to an extract of M. ulcerans (burulin) on skin testing, indicating a degree of T-cell sensitization, the close correlation between reactors to burulin and purified protein derivative suggests that sensitization is due to cross-reactivity with other mycobacterial species (17).A soluble lipid product, called mycolactone, produced by M. ulcerans produces cutaneous histological lesions in guinea pigs similar to those observed in patients with M. ulcerans disease (5). Mycolactone also exhibits immunosuppressive properties in vitro, manifested by suppression...

Superantigens are important virulence factors in the pathogenesis of invasive disease caused by group A streptococcus (GAS). There has been a recent re-emergence of this disease worldwide. A number of novel superantigens have been described recently. This study investigated 107 isolates of GAS for possession of each of the 11 currently known superantigen genes to determine the prevalence, co-occurrence and genetic restriction amongst different emm types of GAS. The results were compared with those in previously published studies. Superantigen genes were not randomly distributed amongst GAS isolates. Certain combinations of superantigen genes were more common and the majority of emm types showed restricted superantigen profiles. This is the first prevalence study of GAS isolates to include the complete range of known superantigen genes and their restriction amongst emm types. This study contributes to the understanding of the relationship between superantigen genes and emm types, and highlights the importance of comprehensive studies in different populations. INTRODUCTIONOver the past 20 years, there has been a significant increase in the incidence of invasive disease caused by group A streptococcus (GAS) (Stevens et al., 1989;Johnson et al., 1992). Superantigens are believed to be important virulence factors of this pathogen. They are extracellular protein toxins that are pyrogenic, increase host susceptibility to endotoxic shock, suppress immunoglobulin production and have mitogenic activity for specific T-cell subsets (Curtis, 1996). This activity leads to extensive immune activation and a massive release of pro-inflammatory cytokines, such as tumour necrosis factor-a, interleukin-6, interleukin-2 and gamma interferon, which can cause shock and widespread organ damage. With the recent sequencing of the complete genomes of the emm1, emm3, emm6, emm18 and emm28 isolates of GAS, a number of novel superantigens have been discovered (Ferretti et al., 2001;Beres et al., 2002;Smoot et al., 2002a;Nakagawa et al., 2003;Banks et al., 2004;Green et al., 2005). A total of 11 superantigens have been identified in GAS to date: streptococcal pyrogenic exotoxin (SPE) A, SPEC, SPEG, SPEH, SPEI, SPEJ, SPEK, SPEL, SPEM, streptococcal mitogenic exotoxin (SME) Z and streptococcal superantigen (SSA).Most GAS superantigen-encoding genes are associated with bacteriophages, except for speG, speJ and smeZ (Proft et al., 2000Ferretti et al., 2001;. The documented prevalence of bacteriophage-encoded superantigens varies widely geographically and temporally. GAS superantigens have also been associated with isolates of particular emm and M types. The emm-type-specific associations are hypothesized to reflect a selective influence of surface M protein on bacteriophage entry (Mylvaganam et al., 2000). The superantigen genes speG, speJ and smeZ are believed to be chromosomally encoded. This is supported by the reported 100 % prevalence of these genes in many studies (Proft et al., 2000McCormick et al., 2001;Smoot et al., 2002a; and a genome s...