Copper homeostasis, protein transport and signal transduction in Bordetella pertussis
Copper is an essential nutrient for aerobic bacteria, notably as a co-factor of superoxide dismutases and cytochrome oxidases, but it is also toxic and used as a killing agent by phagocytes. Unlike other Gram-negative bacteria, the host-restricted pathogen Bordetella pertussis has few defenses against copper other than a custom-made system that fends off both metal and oxidative stresses. Conversely, this bacterium has acquired an original two-protein copper acquisition system that we are currently investigating, composed of a TonB-dependent transporter and a heme-containing inner membrane protein of unknown function.  We have discovered a sophisticated mode of regulation of this system by copper that involves a novel upstream Open Reading Frame (‘uORF’). We have also identified a new family of ribosomally produced, post-translationally modified peptides (‘RiPPs’) that participate in copper homeostasis, in B. pertussis and other pathogenic and environmental bacteria. In the ANR grant CuRiPP we are studying the activity, the structure and the chemical modifications of these natural products using microbiological and biophysical approaches. We are also pursuing our investigations on the structural dynamics of FhaC, the model transporter of the Two-Partner protein Secretion pathway using cryo-electron microscopy, in the ANR grant OPEN BAR.  Finally, we are trying to obtain the cryo-electron microscopy structure of BvgS, the sensor-kinase of the two-component system that regulates the virulence of B. pertussis. BvgS represents a large family of complex bacterial signaling proteins.

Intracellular fate of respiratory pathogens within alveolar macrophages
Mycobacteria are predominantly intracellular pathogens and develop mechanisms to prevent intracellular degradation and to survive inside infected cells. Bordetella pertussis on the other side is a transient intracellular pathogen, the majority of which are killed by host cells within a couple of days.  
We recently became interested in studying molecular and cellular mechanisms involved in the degradation and/or survival of these two pathogens inside alveolar macrophages.  Once the respiratory pathogens are inhaled, they will encounter phagocytic cells which represent a first line of defense against the infection. Among them, alveolar macrophages play a key role in protection.  Xenophagy represents a highly conserved defense mechanism of eukaryotic cells involved in the clearance of invading pathogens. During this complex process, intracellular micro-organisms are targeted to the degradative lysosomal compartment. A non-canonical autophagic pathway through LC3-associated phagocytosis (LAP) also contributes to immune regulation and inflammatory responses.
A knowledge gap exists on the involvement of autophagy and/or LAP in the intracellular clearance of B. pertussis and its impact on innate immune responses. On the other hand, while the mechanisms leading to intracellular survival of M. tuberculosis are extensively studied, little is known on the intracellular fate of ancestral mycobacteria and the evolutionary mechanisms leading to intracellular persistence.
We established a novel partnership with Dr. Ghaffar Muharram (MCPI team, CIIL) to tackle this question.