Immunosuppression and treatment-associated inflammatory response in patients withMycobacterium ulceransinfection (Buruli ulcer)

Abstract

Buruli ulcer is a necrotizing skin disease caused by Mycobacterium ulcerans . Major necrosis with abundant clusters of extracellularly replicating mycobacteria and only minor leukocyte infiltration are characteristic histopathologic features of the disease. Mycolactone, a cytotoxic macrolide exotoxin of M. ulcerans , plays a key role in the development of this pathology. Antimicrobial therapy, such as rifampicin/streptomycin that was recently introduced, seems to lead to phagocytosis of mycobacteria and massive leukocyte infiltration, which culminates in the development of ectopic lymphoid structures in the lesions. Whereas the curative effect of the antibiotic treatment may be supported by immune defense mechanisms, persisting mycobacterial antigens and immunostimulators occasionally also seem to cause apparent reactivation of the disease. This seems to be related to excessive immunostimulation rather than to incomplete killing of the pathogen.

Severe Multifocal Form of Buruli Ulcer after Streptomycin and Rifampin Treatment: Comments on Possible Dissemination Mechanisms

“…Several reports have described a similar excessive immune response following effective antimycobacterial therapy. [20][21][22] This phenomenon, called "paradoxical reaction" 22 or "immune reconstitution inflammatory syndrome (IRIS)," has also been described in patients with HIV who are coinfected with other mycobacteria, such as Mycobacterium tuberculosis or Mycobacterium leprae . 23,24 Although our patient was HIV-negative, the IRIS is highly supported by the clinical characteristics (fever, swelling, or abscess) previously described, 20,[24][25][26] the increase in the WBC count, the alpha-1, alpha-2, and gamma globulin values ( Table 2 ), and the histopathologic results.…”

Pleiotropic molecular effects of theMycobacterium ulceransvirulence factor mycolactone underlying the cell death and immunosuppression seen in Buruli ulcer

“…But how this relates to expression in its environmental niche (itself not clearly defined) or during different stages of clinical ulcers is not known. What is clear, however, is that during antibiotic treatment of patients with advanced ulcers, a non-inflammatory immunohistochemistry reverts to a granulomatous pattern more similar to that seen in other mycobacterial infections (such as M. tuberculosis, M. leprae and M. marinum M), possibly suggesting that rifampicin/streptomycin are able to switch off mycolactone production as part of the mycobacteriocidal activity [21]. On the other hand, mycolactone has been successful isolated from ulcer exudates of patients who have completed a sterilising course of antibiotic therapy [22] and also persists in experimental infections [23].…”

Mycobacterium ulcerans Disease (Buruli Ulcer): Potential Reservoirs and Vectors

“…In more advanced stages, mycolactone is thought to mediate the killing of host cells and infiltrating leukocytes. Subsequent extracellular multiplication of the bacteria, producing a protective cloud of mycolactone, leads to the characteristic histopathology of clumps of extracellular bacteria surrounded by necrosis of the deep dermal and adipose tissue associated with limited inflammatory response [77]. Future research should be targeted at unraveling protective immune defense mechanisms against M. ulcerans and the development of improved vaccination strategies, including mycolactone-targeting vaccines, attenuated live vaccines or subunit protein vaccines.…”