scholarly journals Vaccine-specific immune responses against Mycobacterium ulcerans infection in a low-dose murine challenge model

2019 ◽  
Author(s):  
Kirstie M. Mangas ◽  
Andrew H. Buultjens ◽  
Jessica L. Porter ◽  
Sarah L. Baines ◽  
Estelle Marion ◽  
...  
Keyword(s):  
Low Dose ◽  
Inflammatory Responses ◽  
Subcutaneous Tissue ◽  
Buruli Ulcer ◽  
Experimental Period ◽  
Mycobacterium Ulcerans ◽  
Prognostic Models ◽  
Infection Model ◽  
Multivariate Statistical ◽  
Immune Parameters

AbstractThe neglected tropical disease Buruli ulcer (BU) is an infection of subcutaneous tissue with Mycobacterium ulcerans. There is no effective BU vaccine. Here, we assessed an experimental prime-boost vaccine in a low-dose murine tail infection model. We used the enoyl-reductase (ER) domain of the M. ulcerans mycolactone polyketide synthases electrostatically coupled with a previously described TLR-2 agonist-based lipopeptide adjuvant, R4Pam2Cys. Mice were vaccinated and then challenged via tail inoculation with 14-20 colony forming units (CFU) of an engineered bioluminescent strain of M. ulcerans. Mice receiving either the experimental ER vaccine or Mycobacterium bovis Bacille Calmette-Guérin (BCG) were equally well protected, with both groups faring significantly better than non-vaccinated animals (p<0.05). A suite of 29 immune parameters were assessed in the mice at the end of the experimental period. Multivariate statistical approaches were then used to interrogate the immune response data to develop disease-prognostic models. High levels of IL-2 and low IFN-γ produced in the spleen best predicted control of infection across all vaccine groups. Univariate logistic regression then revealed vaccine-specific profiles of protection. High titres of ER-specific IgG serum antibodies together with IL-2 and IL-4 in the draining lymph node (DLN) were associated with protection induced by the experimental ER vaccine. In contrast, high titres of IL-6, TNF-α, IFN-γ and IL-10 in the DLN and low IFNγ titres in the spleen were associated with protection following BCG vaccination. This study suggests an effective BU vaccine must induce localized, tissue-specific immune profiles with controlled inflammatory responses at the site of infection.

scholarly journals Vaccine-Specific Immune Responses against Mycobacterium ulcerans Infection in a Low-Dose Murine Challenge Model

2019 ◽  
Vol 88 (3) ◽  
Author(s):  
Kirstie M. Mangas ◽  
Andrew H. Buultjens ◽  
Jessica L. Porter ◽  
Sarah L. Baines ◽  
Estelle Marion ◽  
...  
Keyword(s):  
Low Dose ◽  
Inflammatory Responses ◽  
Subcutaneous Tissue ◽  
Interleukin 2 ◽  
Mycobacterium Ulcerans ◽  
Prognostic Models ◽  
Effective Vaccine ◽  
Infection Model ◽  
Content Type ◽  
Ifn Γ

ABSTRACT The neglected tropical disease Buruli ulcer (BU) is an infection of subcutaneous tissue with Mycobacterium ulcerans. There is no effective vaccine. Here, we assessed an experimental prime-boost vaccine in a low-dose murine tail infection model. We used the enoyl reductase (ER) domain of the M. ulcerans mycolactone polyketide synthases electrostatically coupled with a previously described Toll-like receptor 2 (TLR-2) agonist-based lipopeptide adjuvant, R4Pam2Cys. Mice were vaccinated and then challenged via tail inoculation with 14 to 20 CFU of a bioluminescent strain of M. ulcerans. Mice receiving either the experimental ER vaccine or Mycobacterium bovis bacillus Calmette-Guérin (BCG) were equally protected, with both groups faring significantly better than nonvaccinated animals (P < 0.05). To explore potential correlates of protection, a suite of 29 immune parameters were assessed in the mice at the end of the experimental period. Multivariate statistical approaches were used to interrogate the immune response data to develop disease-prognostic models. High levels of interleukin 2 (IL-2) and low gamma interferon (IFN-γ) produced in the spleen best predicted control of infection across all vaccine groups. Univariate logistic regression revealed vaccine-specific profiles of protection. High titers of ER-specific IgG serum antibodies together with IL-2 and IL-4 in the draining lymph node (DLN) were associated with protection induced by the ER vaccine. In contrast, high titers of IL-6, tumor necrosis factor alpha (TNF-α), IFN-γ, and IL-10 in the DLN and low IFN-γ titers in the spleen were associated with protection following BCG vaccination. This study suggests that an effective BU vaccine must induce localized, tissue-specific immune profiles with controlled inflammatory responses at the site of infection.

scholarly journals Chemotherapy-Associated Changes of Histopathological Features of Mycobacterium ulcerans Lesions in a Buruli Ulcer Mouse Model

2011 ◽  
Vol 56 (2) ◽  
pp. 687-696 ◽  
Author(s):  
Marie-Thérèse Ruf ◽  
Daniela Schütte ◽  
Aurélie Chauffour ◽  
Vincent Jarlier ◽  
Baohong Ji ◽  
...  
Keyword(s):  
B Lymphocyte ◽  
Buruli Ulcer ◽  
Mycobacterium Ulcerans ◽  
Infection Model ◽  
Histopathological Study ◽  
Content Type ◽  
Histopathological Features ◽  
Treatment Regimens ◽  
Mouse Infection Model ◽  
New Treatment

ABSTRACTCombination chemotherapy with rifampin and streptomycin (RIF-STR) for 8 weeks is currently recommended by the WHO as the first-line treatment forMycobacterium ulceransinfection (Buruli ulcer). To gain better insight into the mode of action of these antibiotics against establishedM. ulceransinfection foci and to characterize recovery of local immune responses during chemotherapy, we conducted a detailed histopathological study ofM. ulcerans-infected and RIF-STR-treated mice. Mice were inoculated withM. ulceransin the footpad and 11 weeks later treated with RIF-STR. Development of lesions during the first 11 weeks after infection and subsequent differences in disease progression between RIF-STR-treated and untreated mice were studied. Changes in histopathological features, footpad swelling, and number of CFU were analyzed. After inoculation withM. ulcerans, massive infiltrates dominated by polymorphonuclear leukocytes developed at the inoculation site but did not prevent bacterial multiplication. Huge clusters of extracellular bacteria located in large necrotic areas and surrounded by dead leukocytes developed in the untreated mice. Chemotherapy with RIF-STR led to a rapid drop in CFU associated with loss of solid Ziehl-Neelsen staining of acid-fast bacilli. Development of B-lymphocyte clusters and of macrophage accumulations surrounding the mycobacteria demonstrated the resolution of local immune suppression. Results demonstrate that the experimentalM. ulceransmouse infection model will be a valuable tool to investigate efficacy of new treatment regimens and of candidate vaccines.

scholarly journals Shortening Buruli Ulcer Treatment with Combination Therapy Targeting the Respiratory Chain and Exploiting Mycobacterium ulcerans Gene Decay

2019 ◽  
Vol 63 (7) ◽  
Author(s):  
Paul J. Converse ◽  
Deepak V. Almeida ◽  
Sandeep Tyagi ◽  
Jian Xu ◽  
Eric L. Nuermberger
Keyword(s):  
Buruli Ulcer ◽  
Oxidase Inhibitor ◽  
Mycobacterium Ulcerans ◽  
Infection Model ◽  
Synergistic Activity ◽  
Content Type ◽  
Drug Regimens ◽  
Long Acting ◽  
Synthase Inhibitor

ABSTRACT Buruli ulcer is treatable with antibiotics. An 8-week course of rifampin (RIF) and either streptomycin (STR) or clarithromycin (CLR) cures over 90% of patients. However, STR requires injections and may be toxic, and CLR shares an adverse drug-drug interaction with RIF and may be poorly tolerated. Studies in a mouse footpad infection model showed that increasing the dose of RIF or using the long-acting rifamycin rifapentine (RPT), in combination with clofazimine (CFZ), a relatively well-tolerated antibiotic, can shorten treatment to 4 weeks. CFZ is reduced by a component of the electron transport chain (ETC) to produce reactive oxygen species toxic to bacteria. Synergistic activity of CFZ with other ETC-targeting drugs, the ATP synthase inhibitor bedaquiline (BDQ) and the bc1:aa3 oxidase inhibitor Q203 (now named telacebec), was recently described against Mycobacterium tuberculosis. Recognizing that M. tuberculosis mutants lacking the alternative bd oxidase are hypersusceptible to Q203 and that Mycobacterium ulcerans is a natural bd oxidase-deficient mutant, we tested the in vitro susceptibility of M. ulcerans to Q203 and evaluated the treatment-shortening potential of novel 3- and 4-drug regimens combining RPT, CFZ, Q203, and/or BDQ in a mouse footpad model. The MIC of Q203 was extremely low (0.000075 to 0.00015 μg/ml). Footpad swelling decreased more rapidly in mice treated with Q203-containing regimens than in mice treated with RIF and STR (RIF+STR) and RPT and CFZ (RPT+CFZ). Nearly all footpads were culture negative after only 2 weeks of treatment with regimens containing RPT, CFZ, and Q203. No relapse was detected after only 2 weeks of treatment in mice treated with any of the Q203-containing regimens. In contrast, 15% of mice receiving RIF+STR for 4 weeks relapsed. We conclude that it may be possible to cure patients with Buruli ulcer in 14 days or less using Q203-containing regimens rather than currently recommended 56-day regimens.

Buruli ulcer: Mycobacterium ulcerans infection

2020 ◽  
pp. 1167-1170
Author(s):  
Bouke de Jong ◽  
Françoise Portaels ◽  
Wayne M. Meyers
Keyword(s):  
Polymerase Chain Reaction ◽  
Subcutaneous Tissue ◽  
Buruli Ulcer ◽  
Central Africa ◽  
Skin Grafting ◽  
Surgical Excision ◽  
Mycobacterium Ulcerans ◽  
West And Central Africa ◽  
Cutaneous Nodule ◽  
Polymerase Chain

Buruli ulcer is caused by Mycobacterium ulcerans, which secretes a cytotoxic and immunosuppressive toxin, mycolactone. The disease is characterized by necrosis of skin, subcutaneous tissue, and bone, and is re-emerging as a potentially disabling affliction of inhabitants of tropical wetlands. Major foci are in West and Central Africa with an increasing focus in Australia, Mexico, South America, and Southeast Asia. It is not contagious; environmental sources include water, vegetation, and insects, with humans probably becoming infected by traumatic introduction of the bacillus into the skin from the overlying M. ulcerans-contaminated surface in most instances. Clinical presentation may be as a cutaneous nodule, undermined ulcer, plaque, or widely disseminated oedematous lesion. Clinical diagnosis is often accurate by experienced clinicians, and smears for acid-fast bacilli, culture, polymerase chain reaction assays, and histopathology are confirmatory. Treatment was formerly by wide surgical excision and skin grafting, yet antibiotics have now been found effective, including an all-oral regimen.

scholarly journals Increasing Experience with Primary Oral Medical Therapy for Mycobacterium ulcerans Disease in an Australian Cohort

2016 ◽  
Vol 60 (5) ◽  
pp. 2692-2695 ◽  
Author(s):  
N. Deborah Friedman ◽  
Eugene Athan ◽  
Aaron L. Walton ◽  
Daniel P. O'Brien
Keyword(s):  
Medical Therapy ◽  
Subcutaneous Tissue ◽  
Buruli Ulcer ◽  
Skin Lesions ◽  
Antimicrobial Treatment ◽  
Mycobacterium Ulcerans ◽  
Content Type ◽  
Southeastern Australia ◽  
Observational Cohort ◽  
Stage 1

ABSTRACTBuruli ulcer (BU) is a necrotizing infection of subcutaneous tissue that is caused byMycobacterium ulceransand is responsible for disfiguring skin lesions. The disease is endemic to specific geographic regions in the state of Victoria in southeastern Australia. Growing evidence of the effectiveness of antibiotic therapy forM. ulceransdisease has evolved our practice to the use of primarily oral medical therapy. An observational cohort study was performed on all confirmedM. ulceranscases treated with primary rifampin-based medical therapy at Barwon Health between October 2010 and December 2014 and receiving 12 months of follow-up. One hundred thirty-two patients were managed with primary medical therapy. The median age of patients was 49 years, and nearly 10% had diabetes mellitus. Lesions were ulcerative in 83.3% of patients and at WHO stage 1 in 78.8% of patients. The median duration of therapy was 56 days, with 22 patients (16.7%) completing fewer than 56 days of antimicrobial treatment. Antibiotic-associated complications requiring cessation of one or more antibiotics occurred in 21 (15.9%) patients. Limited surgical debridement was performed on 30 of these medically managed patients (22.7%). Cure was achieved, with healing within 12 months, in 131 of 132 patients (99.2%), and cosmetic outcomes were excellent. Primary rifampin-based oral medical therapy forM. ulceransdisease, combined with either clarithromycin or a fluoroquinolone, has an excellent rate of cure and an acceptable toxicity profile in Australian patients. We advocate for further research to determine the optimal and safest minimum duration of medical therapy for BU.

scholarly journals Infection with Mycobacterium ulcerans Induces Persistent Inflammatory Responses in Mice

2005 ◽  
Vol 73 (10) ◽  
pp. 6299-6310 ◽  
Author(s):  
Martinha S. Oliveira ◽  
Alexandra G. Fraga ◽  
Egídio Torrado ◽  
António G. Castro ◽  
João P. Pereira ◽  
...  
Keyword(s):  
Skin Disease ◽  
Inflammatory Responses ◽  
Buruli Ulcer ◽  
Inflammatory Cells ◽  
Mycobacterium Ulcerans ◽  
Secondary Necrosis ◽  
Systemic Immunosuppression ◽  
Inflammatory Infiltrates

ABSTRACT Buruli ulcer (BU) is a devastating, necrotizing, tropical skin disease caused by infections with Mycobacterium ulcerans. In contrast to other mycobacterioses, BU has been associated with minimal or absent inflammation. However, here we show that in the mouse M. ulcerans induces persistent inflammatory responses with virulence-dependent patterns. Mycolactone-positive, cytotoxic strains are virulent for mice and multiply progressively, inducing both early and persistent acute inflammatory responses. The cytotoxicity of these strains leads to progressive destruction of the inflammatory infiltrates by postapoptotic secondary necrosis, generating necrotic acellular areas with extracellular bacilli released by the lysis of infected phagocytes. The necrotic areas, always surrounded by acute inflammatory infiltrates, expand through the progressive invasion of healthy tissues around the initial necrotic lesions by bacteria and by newly recruited acute inflammatory cells. Our observations show that the lack of inflammatory infiltrates in the extensive areas of necrosis seen in advanced infections results from the destruction of continuously produced inflammatory infiltrates and not from M. ulcerans-induced local or systemic immunosuppression. Whether this is the mechanism behind the predominance of minimal or absent inflammatory responses in BU biopsies remains to be elucidated.

Buruli ulcer: Mycobacterium ulcerans infection

2010 ◽  
pp. 848-850
Author(s):  
Wayne M. Meyers ◽  
Bouke de Jong ◽  
Françoise Portaels
Keyword(s):  
South America ◽  
East Asia ◽  
Subcutaneous Tissue ◽  
Buruli Ulcer ◽  
Central Africa ◽  
Mycobacterium Ulcerans ◽  
South East Asia ◽  
Tropical Wetlands ◽  
West And Central Africa ◽  
Water Vegetation

Buruli ulcer is caused by Mycobacterium ulcerans, which secretes a cytotoxic and immunosuppressive toxin, mycolactone. The disease is characterized by necrosis of skin, subcutaneous tissue, and bone, and is re-emerging as a potentially disabling affliction of inhabitants of tropical wetlands. Major foci are in West and Central Africa, but there are minor endemic foci in Australia, Mexico, South America, and South-East Asia. It is not contagious; environmental sources include water, vegetation, and insects, with humans probably becoming infected by traumatic introduction of the bacillus into the skin from the overlying ...

scholarly journals Cutaneous Mycobacterial Infections

2018 ◽  
Vol 32 (1) ◽  
Author(s):  
Carlos Franco-Paredes ◽  
Luis A. Marcos ◽  
Andrés F. Henao-Martínez ◽  
Alfonso J. Rodríguez-Morales ◽  
Wilmer E. Villamil-Gómez ◽  
...  
Keyword(s):  
Subcutaneous Tissue ◽  
Buruli Ulcer ◽  
Mycobacterium Ulcerans ◽  
Mycobacterial Species ◽  
Content Type ◽  
Cutaneous Infections ◽  
Mycobacterial Infections ◽  
Rapidly Growing Mycobacteria ◽  
Cutaneous Tuberculosis ◽  
Mycobacterium Lepromatosis

SUMMARYHumans encounter mycobacterial species due to their ubiquity in different environmental niches. In many individuals, pathogenic mycobacterial species may breach our first-line barrier defenses of the innate immune system and modulate the activation of phagocytes to cause disease of the respiratory tract or the skin and soft tissues, sometimes resulting in disseminated infection. Cutaneous mycobacterial infections may cause a wide range of clinical manifestations, which are divided into four main disease categories: (i) cutaneous manifestations ofMycobacterium tuberculosisinfection, (ii) Buruli ulcer caused byMycobacterium ulceransand other related slowly growing mycobacteria, (iii) leprosy caused byMycobacterium lepraeandMycobacterium lepromatosis, and (iv) cutaneous infections caused by rapidly growing mycobacteria. Clinically, cutaneous mycobacterial infections present with widely different clinical presentations, including cellulitis, nonhealing ulcers, subacute or chronic nodular lesions, abscesses, superficial lymphadenitis, verrucous lesions, and other types of findings. Mycobacterial infections of the skin and subcutaneous tissue are associated with important stigma, deformity, and disability. Geography-based environmental exposures influence the epidemiology of cutaneous mycobacterial infections. Cutaneous tuberculosis exhibits different clinical phenotypes acquired through different routes, including via extrinsic inoculation of the tuberculous bacilli and dissemination to the skin from other sites, or represents hypersensitivity reactions toM. tuberculosisinfection. In many settings, leprosy remains an important cause of neurological impairment, deformity, limb loss, and stigma.Mycobacterium lepromatosis, a mycobacterial species related toM. leprae, is linked to diffuse lepromatous leprosy of Lucio and Latapí.Mycobacterium ulceransproduces a mycolactone toxin that leads to subcutaneous tissue destruction and immunosuppression, resulting in deep ulcerations that often produce substantial disfigurement and disability.Mycobacterium marinum, a close relative ofM. ulcerans, is an important cause of cutaneous sporotrichoid nodular lymphangitic lesions. Among patients with advanced immunosuppression,Mycobacterium kansasii, theMycobacterium avium-intracellularecomplex, andMycobacterium haemophilummay cause cutaneous or disseminated disease. Rapidly growing mycobacteria, including theMycobacterium abscessusgroup,Mycobacterium chelonei, andMycobacterium fortuitum, are increasingly recognized pathogens in cutaneous infections associated particularly with plastic surgery and cosmetic procedures. Skin biopsies of cutaneous lesions to identify acid-fast staining bacilli and cultures represent the cornerstone of diagnosis. Additionally, histopathological evaluation of skin biopsy specimens may be useful in identifying leprosy, Buruli ulcer, and cutaneous tuberculosis. Molecular assays are useful in some cases. The treatment for cutaneous mycobacterial infections depends on the specific pathogen and therefore requires a careful consideration of antimicrobial choices based on official treatment guidelines.

scholarly journals Telacebec for Ultrashort Treatment of Buruli Ulcer in a Mouse Model

2020 ◽  
Vol 64 (6) ◽  
Author(s):  
Deepak V. Almeida ◽  
Paul J. Converse ◽  
Till F. Omansen ◽  
Sandeep Tyagi ◽  
Rokeya Tasneen ◽  
...  
Keyword(s):  
Plasma Concentrations ◽  
Buruli Ulcer ◽  
Standard Of Care ◽  
Mycobacterium Ulcerans ◽  
Infection Model ◽  
Duration Of Treatment ◽  
Current Standard ◽  
Content Type ◽  
Dose Ranging ◽  
Culture Negative

ABSTRACT Telacebec (Q203) is a new antitubercular drug with extremely potent activity against Mycobacterium ulcerans. Here, we explored the treatment-shortening potential of Q203 alone or in combination with rifampin (RIF) in a mouse footpad infection model. The first study compared Q203 at 5 and 10 mg/kg doses alone and with rifampin. Q203 alone rendered most mouse footpads culture negative in 2 weeks. Combining Q203 with rifampin resulted in a relapse-free cure 24 weeks after completing 2 weeks of treatment, compared to a 25% relapse rate in mice receiving RIF with clarithromycin, the current standard of care, for 4 weeks. The second study explored the dose-ranging activity of Q203 alone and with RIF, including the extended activity of Q203 after treatment discontinuation. The bactericidal activity of Q203 persisted for ≥ 4 weeks beyond the last dose. All mice receiving just 1 week of Q203 at 2 to 10 mg/kg were culture negative 4 weeks after stopping treatment. Mice receiving 2 weeks of Q203 at 0.5, 2, and 10 mg/kg were culture negative 4 weeks after treatment. RIF did not increase the efficacy of Q203. A pharmacokinetics substudy revealed that Q203 doses of 2 to 10 mg/kg in mice produce plasma concentrations similar to those produced by 100 to 300 mg doses in humans, with no adverse effect of RIF on Q203 concentrations. These results indicate the extraordinary potential of Q203 to reduce the duration of treatment necessary for a cure to ≤ 1 week (or 5 doses of 2 to 10 mg/kg) in our mouse footpad infection model and warrant further evaluation of Q203 in clinical trials.

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