Infiltrating leukocytes surround early Buruli ulcer lesions, but are unable to reach the mycolactone producing mycobacteria

Ruf, Marie‐Thérèse; Steffen, Christina M.; Bolz, Miriam; Schmid, Peter; Pluschke, Gerd

doi:10.1080/21505594.2017.1370530

Cited by 33 publications

(50 citation statements)

References 46 publications

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“…Osteomyelitis may occur, as the result of a haematogenous seeding of bacteria from distant foci of infection [Walsh et al., ]. The core of BU lesions, harbouring clusters of extracellular bacilli, is typically devoid of inflammatory infiltrates [Guarner et al., ; Ruf et al., ]. BU is efficiently treated by a combination of the antibiotics rifampicin and streptomycin administered daily for 8 weeks, sometimes associated with surgical excision of lesional skin and skin grafting [Etuaful et al., ; Nienhuis et al., ].…”

Section: Buruli Ulcer the Third Most Common Mycobacterial Diseasementioning

confidence: 99%

Sec61 blockade by mycolactone: A central mechanism in Buruli ulcer disease

Demangel

High

2018

Biology of the Cell

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Infection with Mycobacterium ulcerans results in a necrotising skin disease known as a Buruli ulcer, the pathology of which is directly linked to the bacterial production of the toxin mycolactone. Recent studies have identified the protein translocation machinery of the endoplasmic reticulum (ER) membrane as the primary cellular target of mycolactone, and shown that the toxin binds to the core subunit of the Sec61 complex. Mycolactone binding strongly inhibits the capacity of the Sec61 translocon to transport newly synthesised membrane and secretory proteins into and across the ER membrane. Since the ER acts as the entry point for the mammalian secretory pathway, and hence regulates initial access to the entire endomembrane system, mycolactone-treated cells have a reduced ability to produce a range of proteins including secretory cytokines and plasma membrane receptors. The global effect of this molecular blockade of protein translocation at the ER is that the host is unable to mount an effective immune response to the underlying mycobacterial infection. Prolonged exposure to mycolactone is normally cytotoxic, since it triggers stress responses activating the transcription factor ATF4 and ultimately inducing apoptosis.

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Section: Buruli Ulcer the Third Most Common Mycobacterial Diseasementioning

confidence: 99%

Sec61 blockade by mycolactone: A central mechanism in Buruli ulcer disease

Demangel

High

2018

Biology of the Cell

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“…These results highlight the local consequences of the disease, as observed with other approaches (7,29). Recent histological studies have shown that B cells accumulate in clusters around the site of M. ulcerans infection (10). B cell infiltrates have been observed under chronic inflammatory skin conditions, including cutaneous leishmaniasis and atopic dermatitis (30,31).…”

Section: Discussionmentioning

confidence: 52%

“…Moreover, the systemic humoral response to M. ulcerans infection is weak (8), and M. ulcerans is poorly recognized by circulating antibodies (9). Histological analyses of patient tissues have shown that Buruli ulcer lesions are surrounded by a massive inflammatory infiltration of leukocytes (10). This local infiltration has been characterized in mice and shown to consist predominantly of phagocytes (mostly macrophages and neutrophils) and lymphocytes (8).…”

Section: Introductionmentioning

confidence: 99%

Skin-specific antibodies neutralizing mycolactone toxin during the spontaneous healing of Mycobacterium ulcerans infection

et al. 2020

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Buruli ulcer, a neglected tropical infectious disease, is caused by Mycobacterium ulcerans. Without treatment, its lesions can progress to chronic skin ulcers, but spontaneous healing is observed in 5% of cases, suggesting the possible establishment of a host strategy counteracting the effects of M. ulcerans. We reveal here a skin-specific local humoral signature of the spontaneous healing process, associated with a rise in antibody-producing cells and specific recognition of mycolactone by the mouse IgG2a immunoglobulin subclass. We demonstrate the production of skin-specific antibodies neutralizing the immunomodulatory activity of the mycolactone toxin, and confirm the role of human host machinery in triggering effective local immune responses by the detection of anti-mycolactone antibodies in patients with Buruli ulcer. Our findings pave the way for substantial advances in both the diagnosis and treatment of Buruli ulcer in accordance with the most recent challenges issued by the World Health Organization.

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“…While BU in humans results in different clinical presentations, pathogenesis in experimentally infected mice usually follows a defined pattern that is shaped by the virulence of the M. ulcerans strain used for infection. Two histopathological hallmarks of the human disease are the presence of large extracellular clusters of AFB and the almost complete absence of inflammatory infiltrates in the center of the lesions [91,92], but not necessarily in the periphery of lesions [93]. While acquiring human tissue specimens from early BU cases is challenging due to practical and ethical reasons [93], the mouse model of M. ulcerans infection allowed to describe the early events in the pathogenesis of M. ulcerans infection in detail.…”

Section: Study Of the Pathogenesis Of Buruli Ulcer And The Immune Resmentioning

confidence: 99%

Buruli Ulcer in Animals and Experimental Infection Models

Bolz

Ruf

2019

Buruli Ulcer

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Naturally infected animals presenting with typical BU lesions have so far only been described in Australia and there only in one major endemic focus, the central coastal Victoria close to Melbourne. Between 1980 and 1985, 11 M. ulcerans positive koalas (Phascolarctos cinereus) in a population of approximately 200 koalas on Raymond Island were described as having ulcers on the face, forearm, rump, groin or foot pad [1, 2]. More recently, examination of common ringtail (Pseudocheirus peregrinus) and common brushtail (Trichosurus vulpecula) possums from Point Lonesdale, a small BU endemic region with a recent human outbreak, revealed that 38% of the analyzed ringtail possums and 24% of the brushtail possums had laboratory-confirmed M. ulcerans skin lesions and/or their feces tested positive for M. ulcerans DNA by PCR. Lesions were found on tails, toes, feet and noses with the majority occurring on the tail [3]. Another study by O'Brien et al. showed that M. ulcerans bacteria were present in possum lesions and from 90% of the animals with lesions, positive cultures could be obtained [4]. The high number of possums with skin lesions suggests that possums may represent an animal reservoir for M. ulcerans in southeastern Australia [3-5]. Sporadically, M. ulcerans positive lesions were also diagnosed in domesticated animals like dogs [6], a cat [7], horses [8] and alpacas [9]. In the dogs, lesions were found on the feet, legs and the rump and diagnosis was done by IS2404 real-time PCR (qPCR). Molecular typing in three animals confirmed that the infection was caused by disease-causing human strains [6]. The cat presented with a lesion on the nose and acid fast bacilli (AFB) staining as well as molecular methods confirmed the infection with M. ulcerans [7]. Despite considerable effort, several studies conducted in Africa were not able to corroborate the findings from Australia [10-12].

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Infiltrating leukocytes surround early Buruli ulcer lesions, but are unable to reach the mycolactone producing mycobacteria

Cited by 33 publications

References 46 publications

Sec61 blockade by mycolactone: A central mechanism in Buruli ulcer disease

Sec61 blockade by mycolactone: A central mechanism in Buruli ulcer disease

Skin-specific antibodies neutralizing mycolactone toxin during the spontaneous healing of Mycobacterium ulcerans infection

Buruli Ulcer in Animals and Experimental Infection Models

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