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Pathogénie Moléculaire des Mycobactéries

Christophe Guilhot

Responsable d'équipe

Les objectifs généraux du groupe Guilhot sont de comprendre pourquoi certaines espèces mycobactériennes, telles que Mycobacterium tuberculosis et Mycobacterium leprae, sont des pathogènes humains mortels et d'utiliser ces connaissances pour proposer de nouvelles façons de les combattre. La biosynthèse et la translocation à la surface bactérienne de lipides spécifiques des espèces pathogènes et leur contribution à la pathogenèse ont été le point de mire de ce groupe au cours des dernières années.

eq.guilhot2017-01.jpg Les lipides bactériens dans le contexte de l'interaction hôte/pathogène constituent un domaine scientifique peu exploré. Les mycobactéries, et en particulier Mycobacterium tuberculosis (MTB), sont parmi les meilleurs exemples de pathogènes bactériens utilisant des lipides pour favoriser la réplication et la persistance chez l'hôte humain. 

Une grande partie de leur génome est consacrée au métabolisme des lipides et à la construction d'une enveloppe cellulaire très complexe contenant une grande variété de composants lipidiques uniques. Plusieurs lipides de surface, situés dans une position idéale pour interagir avec les cellules hôtes, sont restreints à un nombre très limité d'espèces mycobactériennes pathogènes. Comprendre comment ces lipides sont construits et transportés vers la surface cellulaire, et comment ils contribuent à la virulence du MTB sont donc des enjeux majeurs dans les domaines de la microbiologie et de la pathogenèse bactérienne.

 

Le groupe Guilhot s'attaque à ces questions depuis plus de 10 ans en utilisant des approches complémentaires en génétique moléculaire, biochimie, microbiologie cellulaire et expérimentation animale. Cette équipe de recherche a élucidé plusieurs voies de biosynthèse de lipide et a proposé plusieurs rôles et mécanismes moléculaires d'action pour les lipides de MTB lors de l'interaction avec les cellules hôtes. Plus récemment, ce groupe a lancé plusieurs nouveaux programmes de recherche pour déchiffrer les étapes de persistance et de transmission du cycle infectieux des bacilles de la tuberculose .

Plus d'information : http://www.ipbs.fr/molecular-mycobacterial-pathogenesis (en anglais)

Chercheurs

Christophe Guilhot

CNRS Research director

Catherine Astarie-Dequeker

CNRS Research associate

Christian Chalut

CNRS Research associate

Kaymeuang Cam

Associate Professor - University of Toulouse

Assistants de recherche

Celine Berrone

European Union H2020 Engineer

Wladimir Malaga

CNRS Engineer

Gautier Prevot

CNRS Fixed-term contract Engineer

Alice Marchand

ANR-funded Engineer

Chercheurs Post-doctoraux

Delphine Payros

Fellow of the Fondation pour la Recherche Médicale

Aideen Allen

ANR Fellow

Doctorants

Laurie Thouvenel

Fellow of the Ministry of Higher Education & Research

Publications

2017

  • Augenstreich J., Arbues, A., Simeone, R., Haanappel, E., Wegener, A., Sayes, F., Le Chevalier, F., Chalut, C., Malaga, W., Guilhot, C., Brosch*, R. and C. Astarie-Dequeker*. (2017) ESX-1 and phthiocerol dimycocerosates of Mycobacterium tuberculosis act in concert to cause phagosomal rupture and host cell apoptosis. Cell. Microbiol. (in press)

2016

  • Arbues A., Malaga, W., Constant, C., Guilhot, C., Prandi*, J. AND C. Astarie-Dequeker*. (2016) The Trisaccharides of Phenolic Glycolipids Confer 1 an Advantage to Major Pathogenic  Mycobacteria through Manipulation of Host-Cell Pattern-Recognition Receptors. ACS Chem. Biol. 11:2865-2875.
  • Burbaud S, Laval F, Lemassu A, Daffé M, Guilhot C and Chalut C (2016). Trehalose polyphleate, are produced by a glycolipid biosynthetic pathway conserved across phylogenetically distant mycobacteria. Cell. Chem. Biol. 23, 1-12.
  • Boritsch E, Frigui W, Cascioferro A, Malaga W, Etienne G, Laval F, Pawlik A, Le Chevalier F, Orgeur M, Ma L, Bouchier C, Stinear TP, Supply P, Majlessi L, Daffé M, Guilhot C and Brosch R (2016). pks5-recombination-mediated cell surface remodelling in Mycobacterium tuberculosis emergence. Nature Microbiol. 1, 15019.

2015

  • Brosch R. and Guilhot C (2015). Les bacilles de la tuberculose bovine: une evolution aux dépens de la transmissibilité chez l’homme. Médecine & Sciences, 31.

2014

  • Arbues A, Lugo-Villarino G, Neyrolles O, Guilhot C and Astarie-Dequeker C (2014). Playing hide-and-seek with host macrophages through the use of mycobacterial cell envelope phthiocerol dimycocerosates and phenol glycolipids. Front. Cell. Infect. Microbiol. 4, 1-7.
  • Gavalda S, Bardou F, Laval F, Bon C, Malaga W, Chalut C, Guilhot C, Mourey L, Daffé M. and Quémard A (2014). One domain may hide another: an acyltransferase function carried by a thioesterase-like domain of polyketide synthase. Chem. Biol. 21, 1660-1669.
  • Gonzalo-Asensio J, Malaga W, Pawlik A, Astarie-Dequeker C, Passemar C, Moreau F, Laval F, Daffé M, Martin C, Brosch R & C Guilhot (2014) Evolutionary history of tuberculosis shaped by conserved mutations in the PhoPR virulence regulator. Proc. Natl. Acad. Sci USA. 111, 11491-11496.
  • Solans L, Gonzalo-Asensio J, Sala C, Benjak A, Uplekar S, Rougemont J, Guilhot C, Malaga W, Martin C and Cole ST (2014). The PhoP-dependent ncRNA Mcr7 modulates the TAT secretion system in Mycobacterium tuberculosis. PLoS Pathog., 10, e1004183. PubMed
  • Caire-Brändli I, Papadopoulos A, Malaga W, Marais D, Canaan S, Thilo L and de Chastellier C (2014). Reversible lipid accumulation and associated division arrest of Mycobacterium avium in lipoprotein (VLDL)-induced foamy macrophages may resemble key events during latency and reactivation of tuberculosis.Infect. Immun., 82, 476-490. PubMed
  • Passemar C, Arbués A, Malaga W, Mercier I, Moreau F, Lepourry L, Neyrolles O, Guilhot C and Astarie-Dequeker C (2014). Multiple deletions in the polyketide synthase gene repertoire of Mycobacterium tuberculosis reveal functional overlap of cell envelope lipids in host-pathogen interactions. Cell. Microbiol., 16, 195-213. PubMed

2013

  • Arbués A, Aguilo JI, Gonzalo-Asensio J, Marinova D, Uranga S, Puentes E, Fernandez C, Parra A, Cardona PJ, Villaplana C, Ausina V, Williams A, Clark S, Malaga W, Guilhot C, Gicquel B and C Martin (2013). Construction, characterization and preclinical evaluation of MTBVAC, the first live-attenuated M. tuberculosis-based vaccine to enter clinical trials. Vaccine, 31, 4867-4873. PubMed
  • Rottier K, Faille A, Prudhomme T, Leblanc C, Chalut C, Cabantous S, Guilhot C, Mourey L, Pedelacq JD (2013). Detection of soluble co-factor dependent protein expression in vivo: application to the 4’-phosphopantetheinyl transferase PptT from Mycobacterium tuberculosis. J. Struct. Biol., 183(3), 320-328.PubMed
  • Martin P, Marcq I, Magistro G, Penary M, Garcie C, Payros D, Boury M, Olier M, Nougayrède J-P, Audebert M, Chalut C, Schubert S and Oswald E (2013). Interplay between siderophores and colibactin genotoxin biosynthetic pathways in Escherichia coli. PLoS Pathog., 9(7), e1003437.PubMed
  • Liu C-F, Tonini L, Malaga W, Beau M, Stella A, Bouyssié D, Jackson MC, Nigou J, Puzo G, Guilhot C, Burlet-Schiltz O and Rivière M (2013). Bacterial protein-O-mannosylating enzyme is crucial for virulence of Mycobacterium tuberculosis. Proc. Natl. Acad. Sci. USA, 110, 6560-6565. PubMed
  • Siméone R, Huet G, Constant P, Malaga W, Lemassu A, Laval F, Daffé M, Guilhot C and Chalut C (2013). Functional characterisation of three O-methyltransferases involved in the biosynthesis of phenolglycolipids in Mycobacterium tuberculosis. PLoS ONE, 8(3), e58954. PubMed

2012

  • Leblanc C, Prudhomme T, Tabouret G, Ray A, Burbaud S, Cabantous S, Mourey L, Guilhot C and Chalut C (2012). 4’-Phosphopantetheinyl transferase PptT, a new drug target required for Mycobacterium tuberculosis growth and persistence in vivo. PLoS Pathog., 8(12), e1003097. PubMed
  • Bergeret F, Gavalda S, Chalut C, Malaga W, Quémard A, Pédelacq J-D, Daffé M, Guilhot C, Mourey L and Bon C (2012). Biochemical and structural study of the atypical acyltransferase domain from the mycobacterial polyketide synthase Pks13. J. Biol. Chem., 287, 33675-33690. PubMed
  • Manca C, Peixoto B, Malaga W, Guilhot C and Kaplan G (2012) Modulation of the cytokine response in human monocytes by Mycobacterium leprae phenolic glycolipid-1 (PGL-1). J. Interferon Cytokines Res., 32(1), 27-33. PubMed

2011

  • Krishna S, Ray A, Dubey SK, Larrouy-Maumus G, Chalut C, Castanier R, Noguera A, Gilleron M, Puzo G, Vercellone A, Nampoothiri KM and Nigou J (2011). Lipoglycans contribute to innate immune detection of mycobacteria. PLoS ONE, 6(12), e28476. PubMed
  • Krishnan N, Malaga W, Constant P, Caws M, Chau TTH, Salmons J, Lan NTN, Bang ND, Daffé M, Young DB, Robertson BD, Guilhot C and Thwaites GE (2011) Mycobacterium tuberculosis lineage influences innate immune response and virulence and is associated with distinct cell envelope lipid profiles. PLoS ONE, 6(9), e23870. PubMed
  • Kirksey MA, Tischler AD, Simeone R, Hisert KB, Uplekar S, Guilhot C, and McKinney JD (2011) Spontaneous loss of phthiocerol dimycocerosates (PDIM) production in Mycobacterium tuberculosis H37Rv.Infect. Immun., 79, 2826-2838. PubMed
  • Neyrolles O and Guilhot C (2011). Recent advances in deciphering the contribution of Mycobacterium tuberculosis lipids to pathogenesis. Tuberculosis, 91, 187-95. PubMed

2010

  • Astarie-Dequeker C, Nigou J, Passemar C, and Guilhot C (2010). The role of mycobacterial lipids in host pathogenesis. Drug Discovery Today: Disease Mechanisms, 7:e33-e41.
  • Tabouret G, Astarie-Dequeker C, Demangel C, Malaga C, Constant P, Ray A, Honoré N, Bello NF, Perez E, Daffé M and Guilhot C (2010). Mycobacterium leprae phenolglycolipid-1 expressed by engineered M. bovis BCG modulates early interaction with human phagocytes. PLoS Pathog., 6:e1001159. PubMed
  • Siméone R, Léger M, Constant P, Malaga W, Marrakchi H, Daffé M, Guilhot C, and Chalut C (2010). Delineation of the roles of FadD22, FadD26 and FadD29 in the biosynthesis of phthiocerol dimycocerosates and related compounds in Mycobacterium tuberculosis. FEBS J., 277:2715-2725. PubMed

2009

  • Méniche X, Labarre C, de Sousa-D’Auria C, Huc E, Laval F, Tropis M, Bayan N, Portevin D, Guilhot C, Daffé M and Houssin C (2009). Identification of a stress-sensing factor of Corynebacterineae that is essential for the mycobacteria physiology. J. Bacteriol., 191:7323-7332. PubMed
  • Huet G, Constant P, Malaga W, Lanéelle M-A, Kremer K, van Soolingen D, Daffé M, and Guilhot C (2009). A lipid profile typifies the Beijing strains of Mycobacterium tuberculosis: identification of a mutation responsible for a modification of the structures of phthiocerol dimycocerosates and phenolic glycolipids. J. Biol. Chem., 284:27101-27113. PubMed
  • Etienne G, Malaga W, Laval F, Lemassu A, Guilhot C and Daffé M (2009). Identification of the polyketide synthase involved in the biosynthesis of cell surface-exposed lipooligosaccharides in Mycobacteria. J. Bacteriol., 191:2613-2621. PubMed
  • Gavalda S, Léger M, van der Rest B, Stella A, Bardou F, Montrozier H, Chalut C, Burlet-Schiltz O, Marrakchi H, Daffé M and Quémard A (2009). The Pks13/FadD32 crosstalk for the biosynthesis of mycolic acids in Mycobacterium tuberculosis. J. Biol. Chem., 284:19255-19264. PubMed
  • Astarie-Dequeker C, Le Guyader L, Malaga W, Seaphanh F-K, Chalut C, Lopez A and Guilhot C (2009). Phthiocerol dimycocerosates of Mycobacterium tuberculosis participate in the invasion of human macrophages by inducing changes in the lipid organization of the plasma membrane. PLoS Pathog., 5:e1000289. PubMed

2008

  • Sinsimer D, Huet G, Manca C, Tsenova L, Koo M-S, Kurepina N, Kana B, Mathema B, Marras SAE, Kreiswirth BN, Guilhot C and Kaplan G (2008). The phenolic glycolipid of Mycobacterium tuberculosis differentially modulates the early host cytokine response but does not in itself confer hypervirulence. Infect. Immun., 76:3027-3036. PubMed
  • Malaga W, Constant P, Euphrasie D, Cataldi A, Daffé M, Reyrat J-M and Guilhot C (2008). Deciphering the genetic bases of the structural diversity of phenolic glycolipids in strains of the Mycobacterium tuberculosis complex. J. Biol. Chem., 283:15177-15184. PubMed

2007

  • Simeone R, Constant P, Malaga W, Guilhot C, Daffé M and Chalut C (2007). Identification of the missing trans-acting enoyl reductase required for the phthiocerol dimycocerosates and phenolglycolipids biosynthesis in Mycobacterium tuberculosis. J. Bacteriol., 189:4597-4602. PubMed
  • Simeone R, Constant P, Malaga W, Guilhot C, Daffé M and Chalut C (2007). Molecular dissection of the biosynthetic relationship between phthiocerol and phthiodiolone dimycocerosates and their critical role in the virulence and permeability of Mycobacterium tuberculosis. FEBS J., 274:1957-1969. PubMed

2006

  • Sacco E, Legendre V, Laval F, Zerbib D, Montrozier H, Eynard N, Guilhot C, Daffé M and Quemard A (2006). Rv3389c from Mycobacterium tuberculosis, a member of the (R)-specific hydratase/dehydratase family. Biochem. Biophys. Act., 1774:303-311. PubMed
  • Chalut C, Botella L, de Sousa-D’Auria C, Houssin C and Guilhot C (2006). The non redundant roles of two 4’-phosphopantheinyl transferases in vital processes of Mycobacteria. Proc. Natl. Acad. Sci. USA, 103:8511-8516. PubMed

2005

  • Portevin D, de Sousa-D’Auria C, Montrozier H, Houssin C, Stella A, Lanéelle, M-A, Bardou F, Guilhot C and Daffé M (2005). The Acyl-AMP ligase FadD32 and AccD4-containing Acyl-CoA carboxylase are required for the synthesis of mycolic acids and essential for the mycobacterial growth. Identification of the carboxylation product and determination of the Acyl-CoA carboxylase components. J. Biol. Chem., 280:8862-8874.PubMed
  • Veyron-Churlet R, Bigot S, Guerrini O, Verdoux S, Malaga W, Daffé M and Zerbib D (2005). The biosynthesis of mycolic acids in Mycobacterium tuberculosis relies on multiple specialized elongation complexes interconnected by specific protein-protein interactions. J. Mol. Biol., 3534:847-58. PubMed

2004

  • Perez E, Constant P, Lemassu A, Laval F, Daffé M and Guilhot C (2004). Characterization of three glycosyltransferases involved in the biosynthesis of the phenolic glycolipid antigens from the Mycobacterium tuberculosis complex. J. Biol. Chem., 279:42574-42583. PubMed
  • Perez E, Constant P, Laval F, Lemassu A, Lanéelle M-A, Daffé M and Guilhot C (2004). Molecular dissection of the role of two methyltransferases in the biosynthesis of phenolglycolipids and phthiocerol dimycoserosate in the Mycobacterium tuberculosis complex. J. Biol. Chem., 279:42584-42592. PubMed
  • Portevin D, de Sousa-D’Auria C, Houssin C, Grimaldi C, Chami M, Daffé M and Guilhot C (2004). A polyketide synthase catalyzes the last condensation step of mycolic acid biosynthesis in mycobacteria and related organisms. Proc. Natl. Acad. Sci. USA, 101:314-319. PubMed

2003

  • Malaga W, Perez E and Guilhot C (2003). Production of unmarked mutations in mycobacteria using site specific recombination. FEMS Microbiol. Lett., 219:261-268. PubMed

2002

  • Constant P, Perez E, Malaga W, Lanéelle M-A, Saurel O, Daffé M and Guilhot C (2002). Role of the pks15/1 gene in the biosynthesis of phenolglycolipids in the Mycobacterium tuberculosis complex: evidence that all strains synthesize glycosylated p-hydroxybenzoic methyl esters and that strains devoid of phenolglycolipids harbor a frameshift mutation in the pks15/1 gene. J. Biol. Chem., 277:38148-38158. PubMed
  • Raynaud C, Guilhot C, Rauzier J, Bordat Y, Pelicic V, Manganelli R, Smith I, Gicquel B and Jackson M (2002). Phospholipase C are involved in the virulence of Mycobacterium tuberculosis. Mol. Microbiol., 45:203-217. PubMed
  • Puech V, Guilhot C, Perez E, Tropis M, Armitige LY, Gicquel B and Daffé M (2002). Evidence for a partial redundancy of the fibronectin-binding proteins for the transfer of mycoloyl residues onto the cell wall arabinogalactan termini of Mycobacterium tuberculosis. Mol. Microbiol., 44:1109-1122. PubMed

2001

  • Camacho LR, Constant P, Raynaud C, Lanéelle M-A, Gicquel B, Daffé M and Guilhot C (2001). Analysis of the phthiocerol dimycoserosate locus of Mycobacterium tuberculosis: evidence that this lipid is involved in the cell wall permeability barrier. J. Biol. Chem., 23:19845-19854. PubMed
  • Perez E, Samper S, Bordat Y, Guilhot C, Gicquel B and Martin C (2001). Essential role for phoP in Mycobacterium tuberculosis virulence. Mol. Microbiol., 41:179-187. PubMed

Book Chapter

  • Guilhot, C. and Daffé, M. (2008) Polyketides and polyketides-containing glycolipids of M. tuberculosis: structure, biosynthesis and biological activities. In S.H.E. Kaufmann & E. J. Rubin (eds), Tuberculosis: Molecular Biology and Biochemistry, Vol. 1 Wiley-Vch Verlag GmBH & Co. KGaA, Weinheim. pp. 21-51.
  • Guilhot, C., Chalut, C. and Daffé M. (2008) Biosynthesis and roles of phenolic glycolipids and related molecules in M. tuberculosis. In M. Daffé & J.-M. Reyrat (eds), The mycobacterial cell envelope. ASM press. Washington, D.C. pp. 273-290.
  • Portevin, D., Malaga, W. and Guilhot C. (2008) The use of temperature sensitive plasmid in mycobacteria. In T. Parish & A. Brown (eds.), Methods in Molecular Biology, Vol. : Mycobacteria Protocols. Humana Press Inc., Totowa, N.J. pp 229-242.
  • Jackson, M., Camacho, L. R., Gicquel, B. and Guilhot C. (2001) Gene replacement and transposon delivery using the negative selection marker sacB. In: « Methods in Molecular Biology: Mycobacterium tuberculosis protocols ». Editors: T. Parish & N. Stocker. Humana Press Inc., Totowa, N.J. pp.1-17.
  • McAdam, R., Quan, S. and Guilhot C. (2000) Mycobacterial transposons and their applications. In: « Molecular Genetics of Mycobacteria ». Editors: G. F. Hatfull & W.R. Jacobs Jr. American Society for Microbiology, Washington, D.C. pp. 69-84. 

Patents & Extensions

Patent title: Use of a 4’-Phopshopantetheinyl Transferases as a target for identifying antibiotic molecules 
Deposit N° EP05292610.2 
Deposit date: 08/12/2005 
Publication N° 1795608 
Proprietors : CNRS, Université P. Sabatier 
Inventors : Christian Chalut, Christophe Guilhot

Extension: 
Patent title: Use of a 4’-Phopshopantetheinyl Transferases as a target for identifying antibiotic molecules 
Priority deposit N° EP05292610.2 
Deposit N° PCT/IB2006004075 
Deposit date: 08/12/2006 
Publication N° WO2007069089 
Proprietors : CNRS, Université P. Sabatier 
Inventors : Christian Chalut, Christophe Guilhot

Patent title: Use of pks 13 protein coding for condensase of mycolic acids of mycobacteria and related strains as an antibiotics target 
Priority deposit N° FR20030010470 
Deposit N° US12/240469 
Deposit date: 29/09/2008 
Publication N° 
Proprietors : CNRS, Université Paris Sud 
Inventors : Christophe Guilhot, Mamadou Daffé, Christine Houssin, Damien Portevin, Célia De Sousa 

Collaborations

Collaborations.jpg

National

  • Roland Brosch, Caroline Demangel, Institut Pasteur (Paris)
  • Priscille Brodin, Franck Lafont, Philip Supply, Institut Pasteur (Lille)
  • Maria-Laura Boschiroli, ANSES (Maison-Alfort)
  • Jean-Louis Herrmann, Université de Versailles St Quentin (Montigny le Bretonneux)
  • Nathalie Winter, INRA (Tours)
  • Thierry Wirth, Museum d’Histoire Naturelle (Paris)

 

International

  • Maria-Cristina Vidal Pessolani, Instituto Oswaldo Cruz (Rio de Janeiro, Brazil)
  • Carlos Martin, Universidad de Zaragoza (Zaragoza, Spain)

Regional

  • Mamadou Daffé, Alain Milon, Lionel Mourey, Olivier Neyrolles, Jérome Nigou, Laurence Salomé, Institut de Pharmacologie et de Biologie Structurale (Toulouse) 
  • Eric Oswald, Institut de Recherche en Santé Digestive (Toulouse)  
  • Yves Génisson, Michel Baltas, Laboratoire de Synthèse et Physiochimie de Molécules d’Intérêt Biologique (Toulouse) 
  • Gwennaële Fichant, Laboratoire de Microbiologie et Génétique Moléculaires (Toulouse)
  • Laurent Kremer, Centre d’Etudes d’Agents Pathogènes et Biotechnologies pour la Santé (Montpellier) 
  • Sylvain Godreuil, Centre Hospitalo-Universitaire (Montpellier)
  • Jean-Yves Bouet, Centre de Biologie Intégrative (Toulouse)

Funding

  • Agence National de la Recherche
  • Fondation pour la Recherche Médical
  • Vaincre la Mucoviscidose
  • Centre National de la Recherche Scientifique
  • Université de Toulouse
  • European Union (H2020)