Mycobacterium ulcerans Triggers T-Cell Immunity followed by Local and Regional but Not Systemic Immunosuppression

Abstract

Buruli ulcer is a neglected infectious disease caused byBuruli ulcer (BU) is an emerging neglected tropical disease caused by Mycobacterium ulcerans and is characterized by nonulcerative lesions that can evolve into severe ulcers (41,70).Infection by M. ulcerans poses a unique challenge for the host immune system due to the secretion of the highly cytotoxic lipidic exotoxin mycolactone (17). Mycolactone has been suggested to suppress the development of local and systemic immune responses by inhibiting cytokine production during active BU (19-21, 42, 72, 75) and compromising T-cell priming by suppressing dendritic cell function (11). However, there are no studies on the association of BU with opportunistic infections, suggesting that the immunosuppressive effects of mycolactone might not be systemic.The observations that active BU occurs in a small proportion of exposed individuals (14, 58) and when it develops frequently heals spontaneously (69) suggest the existence of protective immunity. Although the protective mechanisms remain largely unknown, several studies support that adaptive cell-mediated immunity (CMI) is relevant for the control of M. ulcerans (reviewed in reference 53). In fact, (i) M. ulcerans has an intramacrophage growth phase (66), (ii) resistance to BU is associated with the development of T helper (Th) 1 type responses and granulomata (10,20,21,23,42,48,63,70,72), (iii) the positivity of the delayed-type hypersensitivity (DTH) burulin test increases from early to advanced phases (15, 31), (iv) the histopathology of healing BU lesions in patients submitted to antibiotic treatment is consistent with CMI (49), (v) Mycobacterium bovis BCG vaccination induces transient protection in humans and in experimental infections (16,55,60,62,68), (vi) infection with HIV increases the risk of developing BU and more aggressive multifocal forms (27, 64), and (vii) the pattern of cytokine expression in BU lesions conforms with CMI and DTH (28,38,67).Therefore, to clarify whether the M. ulcerans infectious process interferes with the development of protective immunity and whether systemic immunosuppression is induced, we monitored the host immune response in the mouse model, not only in the primary site of infection but also in the draining lymph node (DLN), where the initiation of the adaptive immunity takes place. MATERIALS AND METHODSAnimals. Eight-week-old female wild-type, nude, and Rag2-deficient mice in a BALB/c background were obtained from Charles River (Barcelona, Spain). Rag-deficient BALB/c mice transgenic for the DO11.10 ␣/␤ T-cell receptor (TCR) were from Anne O'Garra (NIMR, London, United Kingdom). The studies involving animals were approved by the review committees of ICVS and the Portuguese Governmental Agency Direcção Geral de Veterinária.Experimental infections. The different M. ulcerans strains used in the present study were selected based on their virulence for mice (35,65) and on the type of mycolactone produced (26, 32, 59). M. ulcerans 5114 is a low-virulence Mexican

Treating Mycobacterium ulcerans disease (Buruli ulcer): from surgery to antibiotics, is the pill mightier than the knife?

“…Thorough reviews documenting existing knowledge as well as audiovisual materials were also produced [51–55]. The decade or so that has followed has been highly productive in terms of research in epidemiology [56], natural history [16,57], diagnostic methods [58,59], immunology [60–63] and vaccine testing [64,65], pathology [66–68], and treatment of this bacterial disease with antibiotics rather than surgery. Very significantly, the M. ulcerans genome was deciphered along with the description of a giant plasmid containing the genes encoding mycolactone [69–71].…”

Buruli ulcer

“…1,8,24,30,60 This has led to improved therapy, 61,62 as well as identification of possible candidates for vaccination and diagnosis. 26,28,51 However, many questions remain to be answered, such as the relative importance of humoral and cellular immune responses in controlling the infection.…”

An Optimized Method for Extracting Bacterial RNA from Mouse Skin Tissue Colonized by Mycobacterium ulcerans

“…M. ulcerans then kills the host macrophage by producing mycolactone, a lipid toxin, initiating an extracellular stage, in which local mycolactone concentrations increase considerably, leading to massive host tissue destruction. During these two stages, mycolactone is not only cytotoxic, it also modulates the immune system, modifying cytokine production and acting on the peripheral nervous system to induce the formation of a painless lesion (George et al, 1999; Coutanceau et al, 2005; Oliveira et al, 2005; Torrado et al, 2007, 2010; Silva et al, 2009; Fraga et al, 2010, 2012; Marion et al, 2014b). These pleiotropic effects of mycolactone facilitate host colonization by this bacillus.…”