IPBS-Toulouse

Molecular Mycobacterial Pathogenesis

Christophe Guilhot
Christophe Guilhot

Group Leader

The overall objectives of our group are to understand what make some mycobacterial species, such as Mycobacterium tuberculosis and Mycobacterium abscessus, such deadly human pathogens and to use this knowledge to propose new ways to fight them. The biosynthesis and translocation to the cell surface of pathogen specific lipids and their contribution to pathogenesis, and the emergence and evolution of mycobacterial pathogens have been the main focus of this group in the recent years.

Our team develops innovative genetic approaches to understand the exceptional epidemic success of tuberculosis bacilli and related mycobacterial pathogens.

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.

Team members

Research Scientists

Kaymeuang Cam (University)
Christian Chalut (CNRS)
Christophe Guilhot (CNRS)

Research Engineers

Jérémy Castagne-Sintes
Marie Devaere
Sophie Manzi (CNRS)

Postdoctoral Fellows

Carlos Adriano de Matos e Silva
Valentin Wasselin

PhD Students

Célia Bernard
Eva Meunier
Grégoire Mongin

Allen et al. (2021) Parallel experimental evolution in mice reveals that increased resistance was a key event for the emergence of persistent tuberculosis bacilli. Nat Microbiol

Augenstreich et al. (2019) The conical shape of DIM lipids promotes Mycobacterium tuberculosis infection of macrophages.  Proc Natl Acad Sci USA

Burbaud et al. (2016) Trehalose polyphleate, are produced by a glycolipid biosynthetic pathway conserved across phylogenetically distant mycobacteria. Cell Chem Biol

Boritsch et al.(2016) pks5-recombination-mediated cell surface remodelling in Mycobacterium tuberculosis emergence. Nat Microbiol

Gonzalo-Asensio et al. (2014) Evolutionary history of tuberculosis shaped by conserved mutations in the PhoPR virulence regulator.  Proc Natl Acad Sci USA

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).