Our team is interested in understanding and analyzing the interactions of pathogens with their host, leading to its infection and possible destruction. Our targets of interest are diverse and include (i) bacteriophages, (ii) type 6 and type 9 secretion systems, and (iii) the host immune response with a particular focus on the role of antibodies.

Understanding host-pathogen interactions is at the heart of the fight against pathogens involved in infectious diseases (viruses, bacteria).

For about ten years, we have been studying the structure and adhesion mechanism of bacteriophages (viruses infecting bacteria) infecting the bacterium used in the milk industry, Lactococcus lactis. We have determined the structures of several phage virions by electron microscopy, and that of the anti-receptors or baseplate (sets of 1-2 Mda), eventually complexed to their receptor, by X-ray diffraction. Still in the field of virology, we have recently launched  a project on the human hepatitis E virus (HEV).

With regard to bacterial infections, we have tackled the study of bacterial secretory systems, in particular those of type VI (T6SS) and type 9 (T9SS). We have determined the structure and interactions of some of the 13 components of T6SS. We aim to reconstruct the entire system using a “hybrid” approach including electron microscopy and X-ray diffraction. The same approach is applied to T9SS.

Alain Roussel’s Research topic – Putting structural studies at the service of a detailed understanding of the mechanisms of life.

The studies we conduct focus on one hand on factors of pathogenicity of bacteria and on the other hand on means of response of host organisms. Our projects can be grouped in 2 scientific disciplines which are immunology and microbiology. 

At the methodological level, X-ray crystallography will remain the basis of all our studies but we are aware of the current developments in the field of structural biology. In particular, the rise of electron microscopy is opening up new avenues. We are also running a camelid antibody generation platform (also called VHH or Nanobody). This tool gives us a significant competitive advantage in tackling most of our projects.

Extracellular vesicles covered by recombinant Ebola GP

Adeline Goulet’s Research topicUnraveling the molecular mechanisms used by bacteriophages to infect their host

Bacteriophages (phages) are the most abundant biological entities on Earth. Yet, these sophisticated bacteria-killing nanomachines remain poorly understood. What has made them so successful?

Our main research interest is, in a pan-phage approach, to unravel the molecular mechanisms deployed by phages upon infection to recognize, puncture, and hijack their host. We use a multi-disciplinary approach including cryo-electron microscopy, X-ray crystallography, and biochemical/biophysical characterization of macromolecular interactions. With these combined investigations we aim to obtain multi-scale information on phage infection modus operandi. This provides us with a comprehensive understanding of phage-bacteria interactions, but not only that, as this knowledge will pave the way towards rational development of phage-based applications for therapeutic, diagnostic and biocontrol purposes.

Reconstruction of the p2 phage in the “resting” and “activated” forms

Isabelle Imbert’s Research topicIdentifying the molecular mechanisms of replication of RNA viruses

RNA viruses are responsible for all emerging infectious diseases (Ebola, Zika, Dengue, Coronaviruses…). Unfortunately, most of the time, we have few weapons to fight them, due to a certain lack of knowledge of their propagation cycle.
Combining multidisciplinary approaches such as biochemistry, enzymology, structural biology combining to artificial intelligence methods, we aim to dissect fascinating RNA virus replication machineries. These data will lay the groundwork for the discovery of anti-viral molecules. Indeed, viral replicases have already proved their worth with, for example, the development of therapies against HIV and HCV.

Model of SARS-CoV processive replication complex

Philippe Leone’s Research topicBacterial secretion system and nematode innate immunity.

Type IX Secretion System (T9SS)

The T9SS is responsible for Porphyromonas gingivalis pathogenesis through secretion of virulence factors, and for Flavobacterium johnsoniae motility through secretion of adhesins. Among the 18 identified proteins that are involved in T9SS function, the K-L-M-N proteins are supposed to form the core complex. We propose that the outer membrane ring-shaped K-N complex serves as an interaction platform to recruit the inner membrane L-M complex, and that the L-M complex is a novel rotary motor driven by proton motive force. Our objective is to solve the structures of the isolated soluble domains of L and N proteins, and of the L-M and K-L-M-N membrane complexes from the two bacterial models, by X-ray crystallography and cryo-EM (in collaboration with Olivier Lambert, ICBMN, Bordeaux). The function of the L-M complex, and notably its role as a rotary motor, will be addressed by in vivo approaches (in collaboration with Eric Cascales, LISM, Marseille).

Scheme of the T9SS in a Gram negative bacteria

C. elegans innate immunity

This project, in collaboration with Jonathan Ewbank (CIML, Marseille), aims at deciphering the host-pathogen relationships between C. elegans and the obligate fungal pathogen Drechmeria coniospora. By RNAi screening on whole C. elegans genome, our collaborators identified 270 genes involved in the nematode innate immunity. Among them, only 33 have no functional annotation, and even fewer are specific to nematodes and are not present in other metazoans. On the other hand, virulence factors from D. coniospora were identified and those not present in other fungi and without functional annotation were selected. Our objective is to solve the structures of the nematode and D. coniospora specific proteins; functional studies are carried out in parallel by our collaborators.

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