IFN-γ–Dependent Activation of Macrophages during Experimental Infections by <i>Mycobacterium ulcerans</i> Is Impaired by the Toxin Mycolactone

Torrado, Egídio; Fraga, Alexandra G.; Logarinho, Elsa; Martins, Teresa G.; Carmona, Jenny Andrea; Gama, José B.; Carvalho, M. Alice; Proença, M. Fernanda; Castro, António G.; Pedrosa, Jorge

doi:10.4049/jimmunol.0902717

Cited by 50 publications

(67 citation statements)

References 66 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Mycolactone has been reported to inhibit macrophage responses (4,12,40,44,54,65,67), the maturation and/or migration of dendritic cells, and consequently T-cell priming (11). Moreover, it has been recently reported that mycolactone injected subcutaneously or produced during experimental M. ulcerans infection was detected in lymphoid organs and in blood mononuclear cells.…”

Section: Discussionmentioning

confidence: 99%

“…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).…”

mentioning

confidence: 99%

See 1 more Smart Citation

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

et al. 2011

Self Cite

View full text Add to dashboard Cite

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

show abstract

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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

et al. 2011

Self Cite

View full text Add to dashboard Cite

show abstract

“…Buruli ulcer is a necrotizing skin infection, with skin lesions caused by mycolactone, the main virulence factor of M. ulcerans. This toxin is endowed with dermonecrotic (destruction of the skin and soft tissues) immunosuppressive activities and analgesic properties facilitating host colonization (3)(4)(5)(6)(7). In the absence of treatment, the lesions may evolve into massive ulcers and, in the most severe cases, bone is affected, leading to massive deformities.…”

mentioning

confidence: 99%

“…Usually, all preclinical studies of M. ulcerans infection are performed in a mouse model, using either BALB/c or C57BL/6 mouse strains, and they study host colonization or evaluate efficacy of treatments or vaccines (7,(10)(11)(12)(13)(14). As a matter of fact, in both strains, s.c. inoculation with M. ulcerans invariably leads to ulceration after several weeks, with lesions evolving toward tissue necrosis and death of the animals.…”

mentioning

confidence: 99%

FVB/N Mice Spontaneously Heal Ulcerative Lesions Induced by Mycobacterium ulcerans and Switch M. ulcerans into a Low Mycolactone Producer

Marion

Jarry

Cano

et al. 2016

The Journal of Immunology

View full text Add to dashboard Cite

Buruli ulcer, a debilitating disease, is caused by Mycobacterium ulcerans. The incidence of this neglected tropical disease is steadily increasing. As a rule, without treatment, skin ulcers occur and a lengthy healing process may be observed associated with severe functional disabilities. Mouse models are already available to study establishment of lesions or evaluation of therapy but a lack of a suitable animal model, mimicking all clinical stages, in particular the healing process, remains an obstacle to understand the pathophysiology of M. ulcerans infection. M. ulcerans was s.c. inoculated in three consanguine mouse strains, that is, BALB/c and C57BL/6, classically used to study mycobacterial infection, and FVB/N. Strikingly, FVB/N mice, although as sensitive as all other mouse strains with respect to M. ulcerans infection, presented a spontaneous healing after the ulcerative phase despite stable bacterial load, and mycolactone toxin was not detected in the healed tissues. The spontaneous healing process was accompanied by an activation of the innate immune system. The adaptive response initiated by FVB/N mice was not involved in the healing process and did not confer protection against M. ulcerans. Our work highlights the importance of innate immune responses to control M. ulcerans infection. This in vivo model of M. ulcerans infection now paves the way for new avenues of research toward the elucidation of critical stages of this disease, such as the characterization of the regulation of mycolactone production, a better understanding of the pathophysiology of M. ulcerans infection, and the development of new therapeutic strategies.

show abstract

“…The findings of generally increased neopterin levels after effective antimicrobial treatment are consistent with results of previous research showing recovery of a typical Th1-type anti-mycobacterial immune response, resulting in a lower bacterial load and a reduced concentration of the immune suppressing toxin produced by M. ulcerans, mycolactone. 6,7 In patients who received antibiotic treatment including clarithromycin, neopterin did not increase as in the patients on streptomycin/rifampicin for eight weeks. This difference in Th1-type immunity response in the group containing clarithromycin treatment may be caused by immunomodulatory effects of clarithromycin.…”

mentioning

confidence: 99%

Serum Levels of Neopterin during Antimicrobial Treatment for Mycobacterium ulcerans Infection

Zeeuw

Duggirala²,

Nienhuis³

et al. 2013

The American Society of Tropical Medicine and Hygiene

View full text Add to dashboard Cite

Abstract. Neopterin is closely associated with activation of the cellular immune system. Neopterin levels differed between controls and patients with Buruli ulcer disease. No differences between patients with or without paradoxical responses were observed. Therefore, neopterin has no value in detecting paradoxical responses among patients with limited Buruli ulcer disease. Neopterin levels were lower in patients receiving clarithromycin. This finding might indicate a slower cellular immune recovery, with possible consequences in future therapy with clarithromycin.Buruli ulcer (BU), which is caused by Mycobacterium ulcerans, is an emerging neglected Tropical Disease reported from more than 30 countries, mainly with tropical and subtropical climates. The region with the highest disease burden is western Africa. The treatment recommendation for BU issued by the World Health Organization is streptomycin in combination with rifampicin for eight weeks, with or without additional surgical debridement or skin grafting.1,2 In BU, paradoxical reactions are common 3 and difficult to distinguish from treatment failure. Neopterin is a stable biomarker. Its production is closely associated with activation of the cellular immune system. 4 Macrophages are stimulated to secrete neopterin by interferon-γ (INF-γ) derived from T lymphocytes. An improved cell-mediated immunity could be followed by a paradoxical response. The objective of this study was to evaluate the levels of neopterin in response to antimicrobial treatment and associated paradoxical responses during M. ulcerans infection.Blood samples were collected and demographic and clinical information was obtained from a subset of patients participating in a randomized controlled trial to compare two antimicrobial regimens in two hospitals in Ghana (BURULICO). 5Participants had early, limited (cross-sectional lesion diameters 10 cm) disease and were followed-up for one year from start of treatment (ClinicalTrials.gov, identifier NCT00321178). Patients who showed treatment failure, received a skin graft, or were co-infected with human immunodeficiency virus were excluded from the study. In this way we were able to measure lesions over time after effective antimicrobial treatment, and any increase in lesion size would probably reflect a paradoxical response. For this study, a paradoxical response is defined to as a lesion that was larger at week 8 than at week 6 for which no intervention was required and healing occurred after one year.Blood was obtained from every patient drawn at two time points: at the start of treatment (baseline T0), and after 8 weeks of antimicrobial therapy (T1). Blood was obtained from ageand sex-matched community controls. Serial acetate sheet tracings and digital images were recorded for every patient at T0 and thereafter once every 2 weeks until week 8. In instances of more than one lesion, the largest lesion was measured for the study. Serum neopterin levels were measured by using an enzymelinked competitive immunosorbent assay (Neopterin ELISA; Im...

show abstract

IFN-γ–Dependent Activation of Macrophages during Experimental Infections by Mycobacterium ulcerans Is Impaired by the Toxin Mycolactone

Cited by 50 publications

References 66 publications

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

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

FVB/N Mice Spontaneously Heal Ulcerative Lesions Induced by Mycobacterium ulcerans and Switch M. ulcerans into a Low Mycolactone Producer

Serum Levels of Neopterin during Antimicrobial Treatment for Mycobacterium ulcerans Infection

Contact Info

Product

Resources

About