Integrated Mycobacterial Pathogenomics  


  HEADDr BROSCH Roland / roland.brosch@pasteur.fr
  MEMBERS CHAPLAIS Emanuel, Dr DEMANGEL Caroline / FARGUES Anne Marie / Dr GUENIN- MACE Laure / Dr HONORE Nadine / PARMENTIER Cécile / Dr. PAWLIK Alexandre / SAINT-JOANIS Brigitte / Dr SIMEONE Roxane / ZOUAOUI-FRIGUI Wafa


  Annual Report

The research undertaken in our unit is centered on genomics and pathogenicity of mycobacteria, in order to uncover novel features of mycobacterial pathogens in relation to evolution and the interaction with the host. Whereas the great majority of mycobacteria are harmless saprophytes, a few species have very efficiently adapted to a pathogenic lifestyle and constitute some of most important human pathogens, such as Mycobacterium tuberculosis, the causative agent of human tuberculosis, Mycobacterium leprae, the cause of leprosy and the emerging pathogen Mycobacterium ulcerans, which causes Buruli ulcer, a most serious skin disease prevalent in West Africa.

Genomics of M. tuberculosis complex members

Genomics and comparative genomics are very powerful ways to get insights into the basic genetic structures that define whether or not a given bacterial strain may act as a pathogen. When the genomes of bacterial strains that show different degrees of virulence or different evolutionary success are compared among each other, factors that are responsible for these differences may then be identified. Our unit is particularly interested in using genomics and comparative genomics for members of the M. tuberculosis complex that show outstanding characteristics. Among the investigated strains are Mycobacterium canettii and other tubercle bacilli with unusual smooth colony morphology, also named M. prototuberculosis. Comparative genome analyses of these rare strains with different phylogenic lineages of the M. tuberculosis complex have the potential to uncover the factors responsible for the outstanding evolutionary success of M. tuberculosis as a human pathogen.

ESX, a secretion system involved in virulence

The second theme of the unit is the genetic and functional characterization of the ESX-1 system in members of the M. tuberculosis complex, which is responsible for the secretion of the prototypic ESX proteins, namely the 6 kDa early secreted antigenic target (ESAT-6) and the 10 kDa culture filtrate protein (CFP-10). The loss of the ESX-1 system causes attenuation and it is thought that this genetic event contributed to the attenuation and safety of the bacille de Calmette et Guérin (BCG) vaccine. Secreted ESX proteins induce a strong T cell mediated immune response, are apparently involved in membrane translocation and/or host–cell lysis and represent key virulence factors. There are four other paralogous ESX systems in M. tuberculosis, some of which are essential for in vitro growth. ESX systems also exist in many other actinobacteria and Gram-positive bacteria, and have recently been suggested to be named type VII secretion system.

Mycolactone, a poliketide toxin from M. ulcerans

The third subject of the unit is focused on the effects of mycolactone, a large class of secondary metabolites encoded by a giant plasmid of M. ulcerans. In previous studies we have shown that mycolactone is a mycobacterial PKS products with potent immunosuppressive activity, which has the unique capacity to modulate dendritic cell functions in a selective manner

Keywords: comparative genomics, ancestral, tuberculosis, virulence, regulation



  Publications

Brosch, R., Gordon, S.V., Garnier, T., Eiglmeier, K., Frigui, W., Valenti, P., Dos Santos, S., Duthoy, S., Lacroix, C., Garcia-Pelayo, C., Inwald, J.K., Golby, P., Nunez Garcia, J., Hewinson, R.G., Behr, M.A., Quail, M.A., Churcher, C., Barrell, B.G., Parkhill, J., and Cole, S.T. (2007) Genome plasticity of BCG and impact on vaccine efficacy. Proc Natl Acad Sci U S A. 104: 5596-5601.

Coutanceau, E., Decalf, J., Martino, A., Babon, A., Winter, N., Cole, S.T., Albert, M.L., and Demangel, C.(2007) Selective suppression of dendritic cell functions by Mycobacterium ulcerans toxin mycolactone. J Exp Med. 204:1395-403.

de Jonge, M.I., Pehau-Arnaudet, G., Fretz, M.M., Romain, F., Bottai, D., Brodin, P., Honore, N., Marchal, G., Jiskoot, W., England, P., Cole, S.T., and Brosch, R. (2007) ESAT-6 from Mycobacterium tuberculosis dissociates from its putative chaperone CFP-10 under acidic conditions and exhibits membrane-lysing activity. J Bacteriol. 189:6028-34

Frigui, W., Bottai, D., Majlessi, L., Monot, M., Josselin, E., Brodin, P., Garnier, T., Gicquel, B., Martin, C., Leclerc, C., Cole, S. T., and Brosch, R. (2008). Control of M. tuberculosis ESAT-6 Secretion and Specific T Cell Recognition by PhoP PLoS Pathog. 4(2): e33 .


Phillips, R., Sarfo, F.S., Guenin-Mace, L., Decalf, J., Wansbrough-Jones, M., Albert, M.L., and Demangel, C. (2009) Immunosuppressive signature of cutaneous Mycobacterium ulcerans infection in the peripheral blood of patients with buruli ulcer disease. J Infect Dis. 200:1675-84.



  Web Site

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Activity Reports 2009 - Institut Pasteur
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