Research

Current projects and main achievements

 
 

Mycolactone and M. ulcerans pathogenicity - Buruli ulcer (BU), caused by M. ulcerans, is the third most common mycobacterial disease after Tuberculosis and Leprosy and represents an emerging global threat. Infection with M. ulcerans leads to the formation of small, painless and non-characteristic pre-ulcerative lesions, which eventually develop into typical ulcers, with massive tissue necrosis. Then, following spontaneous resolution or treatment, there is a healing stage that often leaves the patients largely incapacitated (see illustration below). Since the late 1980s, the disease has been increasing dramatically throughout West and Central Africa, prompting the WHO to initiate an awareness and control campaign in 1998 (http://www.who.int/buruli/en/). Although major advances have been made since then regarding the management of the disease with antibiotic therapy, knowledge on the pathogenesis of BU remains limited. To develop new tools for early diagnosis and treatment, it is essential that we uncover the mechanisms of M. ulcerans persistence in vivo.
 

 

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BU disease progression from the pre-ulcerative to healing stages. Coloured shapes illustrate the extent of the progression for bacterial load, necrosis and inflammatory responses (from Demangel et al., Nature Rev Microbiol. 2009)

 
 

A distinctive feature of M. ulcerans among human pathogens is the production of mycolactone, a macrocyclic polyketide playing a critical role in bacterial virulence. Mycolactone is essential for bacterial virulence and sufficient to induce BU-like lesions in intradermally-injected animal models that are characterized by massive cell death and lack of inflammation. How mycolactone mediates this paradoxical combination of effects is still unknown. Over the past few years, we have extensively studied the biological properties of mycolactone in vitro and in animal models.

 
 

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Mycolactone structure (A/B form)

We have shown that mycolactone diffuses into the cytoplasm and kills any type of mammalian cell. In addition, mycolactone alters at non-cytopathic doses key functions of immune cells.
 

It suppresses the maturation, migration and selective production of inflammatory chemokines by dendritic cells, and also impairs the functional biology and homing properties of T lymphocytes. Mycolactone therefore acts by de-structuring the tissues colonized by M. ulcerans and by suppressing the development of innate and adaptive immune responses to infection (see illustration below). We are no trying to identify the molecular targets of mycolactone, and elucidate the mechanisms underlying its various properties.

 

 

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Proposed mechanism of Mycolactone activity in vivo

 
 

In parallel with this fundamental axis, we collaborate with clinicians in endemic areas to design mycolactone-based detection assays for the early diagnosis of BU, and identify immunological correlates of the disease of interest to assist the optimization of antibiotic therapies. We are also involved in a large consortium of European and African laboratories called Burulivac, trying to design vaccines against BU.

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Phenolic glycolipid-1 (PGL-1) and Mycobacterium leprae infectivity- Leprosy is an infectious, neurodegenerative disease of humans caused by M. leprae. Lepromatous leprosy, the most severe manifestation of leprosy, is characterized by poor cellular responses and uncontrolled proliferation of the bacilli throughout the skin.

 
 
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http://www.who.int/topics/leprosy/en/


PGL-1 structure :
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The lack of inflammatory infiltrates around heavily infected macrophages in lesions suggests that M. leprae evades immune recognition. Among the molecules suspected to be critical in this process is the phenolic glycolipid 1 (PGL-1), a compound produced in large quantities by M. leprae in vivo. PGL-1 consists of a lipid core formed by a long-chain b-diol, which occurs naturally as a diester of polymethyl-branched fatty acids. This core is w-terminated by an aromatic nucleus that is glycosylated by a trisaccharide, which is highly specific of M. leprae.

 
 

Until recently, studies on the biological function of PGL-1 were limited by the inability to grow M. leprae in vitro and to genetically engineer this bacterium. Within the frame of an ANR collaborative research programme, seven enzymatic steps were reprogrammed in M. bovis BCG to make it synthesize and display PGL-1 in the cell envelope. Using this strain, we showed that PGL-1 confers capacity to exploit complement receptor 3 (CR3) for efficient invasion of human macrophages and evasion of inflammatory responses, and provided evidence that PGL-1 promotes bacterial uptake by human dendritic cells and suppresses infection-induced cell maturation. We are currently investigating which signalling pathways are impacted and what are the consequences of this interaction on immune cell functions.

 
Updated on 12/02/2014

Contact

logo_unitexccx81.jpgDr C. Demangel

 

Unité d’Immunobiologie de l’Infection

Département d’Immunologie

 

INSTITUT PASTEUR

25, rue du Docteur Roux

75724 PARIS Cedex 15, FRANCE
 

Office tel: +33 (0)1 40 61 30 66

Lab tel : +33 (0)1 40 61 38 92

E-mail : caroline.demangel@pasteur.fr

 

Administrative assistant:

Mme Viviane Bustanoby

Tel: +33 (0)1 40 61 33 96

viviane.bustanoby@pasteur.fr

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Our laboratory is located on the 5th floor of the Bâtiment Metchnikoff (building #67 on the map below), room 5041, on the Institut Pasteur Paris campus.

The nearest subway station is “Pasteur” on the lines 6 and 12. 

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