Molecular Mycobacterial Pathogenesis

Tuberculosis (TB) remains a major cause of death worldwide. Our goal is to better understand the basic biology of the causative organism, Mycobacterium tuberculosis, and the specific adaptations and factors underpinning the exceptional capacity of this pathogen to persist within the host and to transmit via aerosol.  

One of the key features contributing to the success of Mycobacterium tuberculosis as a human pathogen is its highly complex cell envelope and the unique structure of some of its constituents. A major focus of our research has been determining how mycobacterial lipids are assembled and translocated to the bacterial cell surface, and how those specific to pathogenic mycobacteria subvert the host immune response to benefit the pathogen. We recently described the biosynthetic pathway for the largest known mycobacterial glycolipids and established its close relationship with that of M. tuberculosis specific lipids. We characterized novel molecular mechanisms of action of mycobacterial lipid virulence factors and found that they modulate the innate immune response either through direct binding to macrophage receptors or through insertion within host membrane. 

A second important area of our research is related to evolution of M. tuberculosis. This microorganism evolved from an environmental ancestor and clonally expanded in the human population.  We explore the emergence of this pathogen and the specific adaptations favoring persistence and aerosol transmission in humans, two major features to explain the epidemic success of M. tuberculosis. We demonstrated that evolution toward a strict pathogenic lifestyle was associated with remodeling of the cell envelope leading to modification of surface lipid composition and to a reduced permeability to toxic molecules.

Finally, although our focus is mostly on TB bacilli, we also expand our studies to another mycobacterial emerging pathogen, Mycobacterium abscessus, to understand the mechanisms explaining its exceptional antibiotic tolerance and its deleterious capacity to colonize the lungs of cystic fibrosis patient.

Our scientific strategy relies on innovative genetic approaches and complementary expertise from the team members in molecular genetics, microbiology, biochemistry, cellular microbiology, and animal experimentation.

Figure Legend: Lung necrotic lesions generated in the murine model by the tubercle bacillus. The sections were stained by the Ziehl-Neelsen method and reveal the bacteria in pink that persist in the core of the necrotic area of the lesion (in blue).

2021

• Laval T, Pedro-Cos L, Malaga W, Guenin-Macé L, Pawlik A, Mayau V, Yahia-Cherbal H, Delos O, Frigui W, Bertrand-Michel J, Guilhot C, and C Demangel. (2021) De novo synthesized polyunsaturated fatty acids operate as both host immunomodulators and nutrients for Mycobacterium tuberculosis. eLife 10:e71946.
• N, Leon-Icaza SA, Knoops K, Sachs N, Mazères S, Simeone R, Peixoto A, Bernard C, Murris-Espin M, Mazières J, Cam K, Chalut C, Guilhot C, López-Iglesias C, Ravelli RBG, Neyrolles O, Meunier E, Lugo-Villarino G, Clevers H, Cougoule C, Peters PJ.(2021) Mycobacteria-host interactions in human bronchiolar airway organoids. Mol. Microbiol. 00:1-11.
• Payros D, Alonso H, Malaga W, Volle A, Mazères S, Déjean S, Valière S, Moreau F, Balor S, Stella A, Combes-Soia L, Burlet-Schiltz O, Bouchez O, Nigou J, Astarie-Dequeker* C and C. Guilhot* (2021) Rv0180c contributes to M. tuberculosis cell shape and to infectivity in mice and macrophages. PLo​​​​​S Pathog. 17:e1010020
• Carivenc C, Maveyraud L,  Blanger C, Ballereau S, Roy-Camille C,  Nguyen MC, Génisson Y, Guilhot C, Chalut C*, Pedelacq JD* and L Mourey*. (2021) Phosphopantetheinyl transferase binding and inhibition by amidino-urea and hydroxypyrimidinethione compounds. Sci. Rep.  11(1):18042.
• Allen AC, Malaga W, Gaudin C, Volle A, Moreau F, Hassan A, Astarie-Dequeker C, Peixoto A, Antoine R, Pawlik A, Frigui W, Berrone C, Brosch R, Supply P and C Guilhot. (2021) Parallel experimental evolution in mice reveals that increased resistance was a key event for the emergence of persistent tuberculosis bacilli. Nature Microbiol. 6(8):1082-1093.
• Schwarz MGA, Antunes D, Corrêa PR, da Silva-Gonçalves AJ, Malaga W, Caffanera ER, Guilhot C and L Mendonça-Lima (2021) Mycobacterium tuberculosis and M. bovis BCG Moreau fumarate reductase operons produce different polypeptides that may be related to non-canonical functions. Front. Microbiol. 11: 624121.

2020

• Grabowska A, Brison, Y, Maveyraud L, Gavalda S, Faille A, Nahoum V, Bon C, Guilhot C, Pedelacq* JD, Chalut* C and L Mourey* (2020) Molecular basis for extender unit specificity of mycobacterial polyketide synthases. ACS Chem. Biol. 15:3206-3216.
• Augenstreich J, Haanappel E, Sayes F, Simeone R, Guillet V, Mazeres S, Chalut C, Mourey L, Brosch R, Guilhot* C, and C Astarie-Dequeker* (2020) Phthiocerol Dimycocerosates from Mycobacterium tuberculosis increase the membrane activity of bacterial effectors and host receptors. Front Cell Infect Microbiol. 10:420.
• Schwarz MGA, Corrêa PR, Malaga W, Guilhot C and L Mendonça-Lima (2020) Mycobacterium bovis BCG moreau is naturally deficient in homologous recombination. Tuberculosis 123:101956.
• Thouvenel L, Prevot G, Chiaradia L, Parra J, Mouton-Barbosa E, Locard-Paulet M, Marcoux J, Tropis M, Burlet-Schiltz O, Daffé M, Guilhot C, Etienne G and C Chalut (2020) The final assembly of trehalose polyphleates takes place within the mycobacterial cell envelope. J. Biol. Chem. 295:11184-11194.
• Alonso MN, Malaga W, Mc Neil M, Jackson M, Romano MI, Guilhot C and MP Santangelo (2020). Efficient method for targeted gene disruption by homologous recombination in Mycobacterium avium subspecie paratuberculosis. Res. Microbiol. 171:203-210.
• Bah A, Sanicas M, Nigou J, Guilhot C, Astarie-Dequeker* C and I Vergne*. (2020) Lipid virulence factors of Myobacterium tuberculosis exert a multilayered control of autophagy-related pathways in infected human macrophages. Cells 9:666.
• Levillain F, Kim H, Kwon KW, Clark S, Cia F, Malaga W, Brodin P, Gicquel B, Guilhot C, Bancroft GJ, Williams A, Shin SJ, Poquet Y and O Neyrolles. (2020). Preclinical assessment of a new live attenuated Mycobacterium tuberculosis Beijing-based vaccine for tuberculosis. Vaccine 38:1416-1423
• Nguyen MC, Saurel O, Carivenc C, Gavalda S, Saitta S, Tran MP, Milon A, Chalut C, Guilhot C, Mourey L and JD Pedelacq. (2020) Conformational flexibility of coenzyme A and its impact on the post-translational modification of acyl carrier proteins by 4’-phosphopantetheinyl transferases. FEBS J. 287:4729-4746

2019

• Doz Deblauwe E, Carreras F, Arbues A, Remot A, Epardaud M, Malaga W, Mayau V, Prandi J, Astarie-Dequeker C, Guilhot C, Demangel C and N Winter. (2019) CR3 engaged by PGL-1 triggers Syk-calcineurin-NFATc to rewire the innate immune response in leprosy. Front. Immunol. 10:2913
• Augenstreich J, Haanappel E., Ferré G., Czaplicki G., Jolibois F., Destainville N., Guilhot C., Milon A., Astarie-Dequeker* C. and M. Chavent*. (2019) The conical shape of DIM lipids promotes Mycobacterium tuberculosis infection of macrophages. Proc. Natl. Acad. Sci USA. 116:25649-25658.

2018

• Diaz Acosta CC, Dias AA, Rosa TLSA, Batista-Silva LR, Rosa PS, Toledo-Pinto TG, Costa FDMR, Lara FA, Rodrigues LS, Mattos KA, Sarno EN, Bozza PT, Guilhot C, de Berrêdo-Pinho M, Vidal-Pessolani, MC. (2018) PGL I expression in live bacteria allows activation of a CD206/PPARγ cross-talk that may contribute to successful Mycobacterium leprae colonization of peripheral nerves. PLOS Pathogens. 14:e1007151.
• Oldenburg R, Mayau V, Prandi J, Arbues A, Astarie-Dequeker C, Guilhot C, Werts C, Winter N and C Demangel. (2018) Mycobacterial phenolic glycolipids selectively disable TRIF-dependent TLR4 signaling in macrophages. Front. Immunol. 9:2

2017

• Kaufmann SHE, et al.  (2017) TBVAC2020: Advancing tuberculosis vaccines from discovery to clinical development. Front. Immunol.  8:1203.
• Alonso H, Parra J, Malaga W, Payros D, Liu C-F, Berrone C, Robert C, Meunier E, Burlet-Schiltz O, Rivière M and C Guillhot. (2017) Protein O-mannosylation deficiency increases LprG-associated lipoarabinomannan release by Mycobacterium tuberculosis and enhances the TLR2-associated inflammatory response. Sci. Rep. 7:7913
• 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. 19:12726

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 C Chalut (2016) Trehalose polyphleate, are produced by a glycolipid biosynthetic pathway conserved across phylogenetically distant mycobacteria. Cell Chem. Biol. 23:278-289.
• 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 R Brosch* (2016) pks5-recombination-mediated cell surface remodelling in Mycobacterium tuberculosis emergence. Nature Microbiol. 1:15019.

All publications and reviews are available through Pubmed  (//pubmed.ncbi.nlm.nih.gov/?term=guilhot+c&sort=date)