Mycobacterium ulcerans toxic macrolide, mycolactone modulates the host immune response and cellular location of M. ulcerans in vitro and in vivo

Abstract

SummaryMycobacterium ulcerans produces an extracellular cutaneous infection (Buruli ulcer) characterized by immunosuppression. This is in stark contrast to all other pathogenic Mycobacteria species that cause intracellular, granulomatous infections. The unique mycobacterial pathology of M. ulcerans infection is attributed to a plasmid-encoded immunomodulatory macrolide toxin, mycolactone. In this article we explore the role of mycolactone in the virulence of M. ulcerans using mycolactone and genetically defined mycolactone negative mutants. In a guinea pig infection model wild-type (WT) M. ulcerans produces an extracellular infection whereas mycolactone negative mutants produce an intracellular inflammatory infection similar to that of Mycobacterium marinum . Although mycolactone negative mutants are avirulent, they persist for at least 6 weeks. Chemical complementation of M. ulcerans mutants with mycolactone restores WT M. ulcerans pathology. Mycolactone negative mutants are capable of growth within macrophages in vitro whereas macrophages are killed by WT M. ulcerans . The ability of mycolactone to caused delayed cell death via apoptosis has been reported. However, mycolactone also causes cell death via necrosis. In vitro mycolactone has antiphagocytic properties. Neither WT M. ulcerans nor mycolactone negative strains are strong neutrophil attractants. These results suggest that mycolactone is largely responsible for the unique pathology produced by M. ulcerans .

The local immune response in ulcerative lesions of Buruli disease

“…In the ulcerative non-granulomatous lesions it was common that bacteria were overlying cells, but in some peripheral areas distant to necrosis we found fewer and dispersed bacilli; in these areas some macrophages showed well-defined intracellular AFB, suggesting real phagocytosed mycobacteria. This observation is in agreement with recent in vitro studies which demonstrated that occasional macrophages can be infected by M. ulcerans [23], and with the concept that M. ulcerans has an intracellular phase that is necessary for the induction of a Th1 immune response [24,25]. It has been demonstrated recently that mycolactone is anti-phagocytic, but macrophages can phagocytose M. ulcerans during early experimental infection and transport the bacilli to the regional lymph nodes [26].…”

“…It has been demonstrated recently that mycolactone is anti-phagocytic, but macrophages can phagocytose M. ulcerans during early experimental infection and transport the bacilli to the regional lymph nodes [26]. Mutant M. ulcerans unable to produce mycolactone is phagocytosed easily by macrophages and induced well-formed granulomas in experimental animal models [23,25,26]. Thus, the few bacilli that we detected in the cytoplasm of macrophages could correspond to dead bacilli or to bacteria which lacked toxin production, facilitating their phagocytosis.…”

Macrolide resistance mechanisms inEnterobacteriaceae: Focus on azithromycin

“…It should be noted that some natural macroliderelated molecules act as toxins, such as mycolactones, which are 12C-membered macrolide lactones. These molecules are produced by different members of the genus Mycobacterium, including Mycobacterium marinum, Mycobacterium pseudoshottsii, Mycobacterium liflandii (Hong et al, 2008;Kishi, 2011;Mve-Obiang et al, 2005;Ranger et al, 2006) or Mycobacterium ulcerans, the most relevant at human clinical level due to the production of a series of mycolactones considered to be responsible for the unique characteristics of Buruli ulcer (Adusumilli et al, 2005). At present, at least nine different M. ulcerans mycolactones have currently been described.…”

Suppressive effect of mycolactone-containing fraction from Mycobacterium ulcerans on antibody production against co-administered antigens

“…Mycolactone inhibits the production of various cytokines, chemokines, and other secreted immune modulators [7] from immune cells such as monocytes [8], macrophages [9], dendritic cells [10], and T cells [11][12][13]. When a mycolactone-deficient strain of M. ulcerans was injected into model animals, a granuloma was successfully developed and the bacteria were cleared from the infected regions [14,15], suggesting that mycolactone has a suppressive effect on cell-mediated immune responses. However, the effects of mycolactone on serum immune responses remain poorly understood.…”