Group leader / Research director (DR-INSERM)
Next-generation therapies against bacterial infections will result from rational exploitation of the genomic sequences of bacterial pathogens, and from a better molecular understanding of their virulence. Our two research streams address these two challenges using two very different bacterial models: Neisseria meningitidis, a diderm species causing meningitis and septicemia, and Streptococcus sanguinis, a monoderm causing endocarditis.
Our first research stream consists in the high-throughput functional analysis of the N. meningitidis genome using a toolbox named NeMeSys. The key module of NeMeSys is an ordered and complete collection of mutants with mutations in each non-essential gene, the only such collection in a bacterial pathogen. Our goal is to generate a global functional map of this important human pathogen.
Our second research stream focuses on type 4 filaments (T4F), key virulence factors in numerous bacterial pathogens. T4F are nano-machines universal in prokaryotes, which mediate a wide variety of functions. We are combining molecular genetics, genomics/phylogenomics, biophysics, and structural biology to study T4F in the above two model species. Our goal is to unravel the molecular mechanisms of T4F biogenesis and of their amazing versatility.
By revealing complete repertoires of genes, genome sequences have provided the key to better, and eventually holistic, understanding of the biology of all living organisms. However, biological resources for identification of gene function on genome-scale, which are necessary to achieve this goal, are often lacking.
As shown in model micro-organisms, the most valuable toolbox for determining gene function on genome-scale is a comprehensive and archived collection with one mutant in each non-essential gene. In bacteria, such collections are available only for a handful species, none of which is pathogenic. One of our long-standing goals has been to create such a resource in N. meningitidis – one of the most feared human bacterial pathogens that causes meningitis and septicaemia – and to use it for large-scale functional profiling of this species genome.
We have therefore designed NeMeSys a modular biological resource for Neisseria meningitidis systematic functional analysis. The main module of NeMeSys is a comprehensive collection of defined meningococcal mutants in strain 8013, consisting of individual mutants in 1,584 non-essential protein-coding genes. We identified 391 essential genes, which are associated with four basic functions (see Figure). We have used NeMeSys to shed light on the functions of multiple genes, and we expect this toolbox to allow, for the first time, the global functional profiling of a major human bacterial pathogen.
Type 4 filaments (T4F) are a superfamily of filamentous nanomachines found on the cell surface of prokaryotes, named after their best-characterised representative type 4 pili (T4P). T4F are filamentous polymers composed of type 4 pilins, assembled by conserved multi-protein machineries (see Figure). Two unique features set T4F apart in the world of prokaryotic filamentous nanomachines. Firstly, they are ubiquitous as T4F genes are found in virtually all bacteria and archaea, which underlines an essential ecological role. Secondly, T4F are exceptionally versatile, mediating adhesion, motility, protein secretion, DNA uptake, swimming etc.
T4F have been studied for decades because they are key virulence factors in many human bacterial pathogens. The best studied bacterial models are diderm proteobacteria, including our historical model N. meningitidis. In recent years, more “exotic” models have emerged, including the monoderm Firmicute S. sanguinis in our lab, an inherently simpler system with two different T4F: T4P and competence pili (see Figure).
For the last 20 years, the PELICIC team has studied several T4F using a multi-disciplinary approach. We have made important contributions to the current understanding of the components of this nanomachine, the way they interact, 3D structures, respective functions etc. Our objective is to unravel, at an atomic level, the molecular mechanisms of filament assembly and of T4F-mediated functions. This will have far-reaching implications in prokaryotes where T4F are ubiquitous.
Group leader / Research director (DR-INSERM)
PhD student (PhD-AMU)
PhD student (PhD-CNRS)