In Europe, Clostridium difficile, a strict anaerobic and sporulating Gram-positive bacterium, is the main cause of nosocomial post-antibiotic intestinal infections in adults. C. difficile infections (CDI) typically occur in patients with altered gut microbiota. C. difficile is responsible for 15 to 25% of diarrhea associated with antibiotic treatments and the majority of pseudomembranous colitis. Our studies focus on i) the adaptive strategies used by C. difficile in response to stresses encountered during infection such as mechanisms of resistance to oxidative/nitrosative stress and biofilm formation; ii) the complex regulatory network of C. difficile sporulation and the relationships that exist between spores and colon cells during colonization; iii) the mechanisms regulating toxin production in response to cellular metabolic pathways and vi) the impact of prophages in the genetic variability of C. difficile strains.

The research conducted in the unit Biologie des Bacteries Intracellulaires (BBI) associated to CNRS (UMR 6047), focuses mainly on pathogenicity related genomic features of the intracellular pathogens Legionella and their function in host-pathogen interactions. Many aspects of this research are based on the studies on Legionella genomics that we have initiated in the last years at the Institut Pasteur.

Our research is linked to the pathophysiology of two major Streptococci, group A (GAS, Streptococcus pyogenes) and B (GBS, Streptococcus agalactiae) Streptococcus, involved in serious invasive infections occurring during pregnancy or the neonatal period. Our goal is to understand why a commensal bacteria in adults is a formidable pathogen in newborns. Finally, we have a public health activity as the National Reference Center for Streptococci (CNR-Strep) which collects clinical data sent by a network of clinical laboratories distributed throughout the national territory and characterizes the strains at the molecular level. responsible for invasive and non-invasive infections.

We study the mechanisms responsible of the bacterial genome variability, with a special interest for those involved in exogenous gene acquisition – the horizontal gene transfer. Our model system is the integron, a natural genetic engineering system involved in the development and dissemination of antibiotic resistance genes among Gram-negative species. We are characterizing the molecular mechanisms in these elements, as well as their evolution and phenotypic impact on host cell physiology.

Scientific activities of the Microbial Evolutionary Genomics Unit are centered on the bioinformatics and biostatistics analysis of genomes, at the crossroads of molecular evolution, population genetics, molecular epidemiology, and molecular genetics. We also develop some translational aspects related with the study of the diversity of bacterial pathogens.

We focus on four major questions:

1. How and why are genomes organized?
2. How are such organizational features evolving in face of the extensive genome dynamics?
3. What are the roles of mobile elements in the evolution of the host genomes?
4. What is the interplay between genome dynamics and bacterial pathogen emergence at the microevolutionary and epidemiological scale?

Our unit conducts fundamental and applied research on bacterial protein toxins with intracellular action on the host. These toxins are involved in the etiology of serious infectious diseases caused by highly pathogenic bacteria or involving multiple antibiotic resistances. In particular, we study botulinum neurotoxins, recognized as the most powerful toxic agents, with the aim of designing and implementing new therapeutic and prophylactic approaches. We also seek to understand the molecular mechanism of action of toxins capable of stimulating pro-oncogenic pathways in the host. These toxins appear to emerge in strains of E. coli are multi-resistant to antibiotics, conferring the ability to colonize the gastrointestinal tract. The E. coli producing these toxins reside in approximately 10% of the general population and are found enriched within the microbiota associated with colorectal cancer. We seek to understand their contribution to the expansion of carrier strains in the populations of industrialized countries and their impact as a risk factor in cancer.

The Unit includes the National Reference Center (CNR) for Salmonella, Shigella/Escherichia coli and the NRC for  Vibrio and Cholera, and a WHO Collaborating Center.  Our research interests are strongly linked to public health and reference activities for the enteric bacterial pathogens monitored by the Unit. We work on three partly overlapping themes: (i) identification and dynamics of bacterial populations resistant to antibiotics (ii) development of new bacterial typing and diagnostic tools, (iii) population structures and the evolution of genetically monomorphic pathogenic agents, with a special focus on emergent, epidemic and antimicrobial-resistant bacterial populations.

We study how a broad range of basic functional processes are modified, and potentially coordinated, to control cellular homeostasis. Our research primarily uses E. coli as a model, but the concepts will also be tested on pathogens such as Salmonella or Shigella. Focusing on two global cellular processes, Fe-S cluster biogenesis and lipid homeostasis, allows us to study the impact of stress on aerobic and anaerobic metabolism, cell envelope homeostasis and membrane, redox changes, nutrient limitation, metabolic stress and antibiotics.
Molecular, biochemical and genetic approaches, as well as cutting-edge technologies (-omics, imaging, single-cell analysis), aim to achieve an integrated and mechanistic vision of the bacterial cell. Multiplying and diversifying the ways of approaching a process is very rewarding, and we collaborate with biochemists, structuralists, chemists, biophysicists, bioinformaticians and phylogeneticists.

Our unit “Dynamics of host pathogen-interactions” develops novel approaches to investigate the interactions between pathogens and their hosts in single cells in real time. In particular, we are interested in deciphering the molecular and cellular basis of how a number of bacterial pathogens, such as Shigella or Salmonella enter host cells during the infection process. To achieve this, we film these invasion events using innovative fluorescence microscopy. We are convinced that deciphering the molecular and cellular details of the invasion strategies used by the bacterial pathogens will identify novel drug targets and will provide new insight into fundamental cell biological processes.

The group is primarily focused on tuberculosis, one of the deadliest human infections and a major a global health emergency . The causative agent, Mycobacterium tuberculosis, is an airborne slow growing microorganism (about 24 hours optimal generation time), which has established a robust association with its host over the course of coevolution. Our group is interested in investigating the molecular basis and the effects of cell-to-cell phenotypic heterogeneity. Is phenotypic heterogeneity crucial to modulate mycobacterial fitness and adaptation during infection? Is there any significant interplay among distinct subpopulations? What is the impact of the microenvironments towards mycobacterial diversification? To answer these and associated questions, we employ a multidisciplinary approach. We use on the one hand classical genetics and conventional microbiology and cell biology assays, and on the other hand single-cell techniques, including FACS and real-time epifluorescent microscopy in combination with custom-built microfluidic systems.

We study the pathogenesis of Neisseria meningitidis (or meningococcus), a Gram-negative bacterium that recapitulates these different pathological effects. Outstanding questions in terms of understanding N. meningitidis pathogenesis include: how do bacteria cross the epithelium and reach the bloodstream? How do they survive in the blood? How do they damage vessels and reach the cerebrospinal fluid (i.e. cause septic shock and meningitis)? These questions open broader studies regarding tissue biology, bacterial adaptation to different environments and basic functions of the innate immune system. We address these questions at different scales.

Our research unit aims at studying peptidoglycan (PGN) metabolism to better understand how bacteria assemble a mature and essential PGN that confers rigidity and shape to the cell despite a highly dynamic process to accompany cell growth and division.

Biofilms are communities of microorganisms that interact with surfaces, and are known to display unique properties that differentiate them from free-floating, individual microorganisms. While biofilms are widespread and play many positive roles in all environments, they are also difficult to eradicate when adhered to surfaces in medical and industrial settings.

We use genetics, genomics, molecular biology, and various in vitro and in vivo biofilm models to better understand biofilm-associated functions used by commensal and pathogenic bacteria. We also attempt to translate our fundamental approaches into relevant anti-biofilm strategies in collaboration with clinicians and industrial partners.

The main goal of our research is to characterize the role of chromatin modifications induced upon bacteria-host interactions and their long term consequences. Our work is at the interface between microbiology, chromatin biology/epigenetics and innate immunity. This multidisciplinary approach will allow the discovery of strategies used by bacteria to reprogram host transcription either during colonization or acute infection, and also provide new insight into fundamental cellular processes such as tolerance to prolonged stimulation and epigenetic memory. In addition, understanding bacteria-induced epigenomic regulation of immune responses could transform our view of immunological memory in vertebrates thereby leading to the development of new antimicrobial agents.

With a surface estimated between 35-70m², the intestine is the main body’s interface. It forms a highly dynamic and tightly regulated barrier that is crucial  to absorb nutrients and fuel our metabolic  needs,  but also to control the vast and complex community of microbes, which colonizes this surface after birth. Our main objective is to dissect how epithelial cells cooperate with immune cells to restrict body access to microbes and undigested food antigens while avoiding deleterious inflammation and tissue damage. In parallel, we analyse the mechanisms by which the  Segmented Filamentous Bacterium orchestrates the post-natal maturation of the gut immune barrier.

Our Unit investigates new pathways and mechanisms involved in the pathogenesis of low GC % Gram-positive bacteria focusing on the major human pathogens Streptococcus agalactiae and Staphylococcus aureus. We also study the emerging pathogen Streptoccus gallolyticus, a cause of septicemia and infective endocarditis in the elderly, which has been consistently linked to colorectal cancer (CRC). Our research topics include the study of i) the relationship between metabolism and virulence, ii) the function of bacterial proteins involved in the interaction with the host, iii) the regulation of virulence gene expression and the adaptation to stressfull environmental conditions, and iv) the genomic diversity and the evolution of pathogens.

The Ecology and Evolution of Antibiotic Resistance (EERA) Unit aims at characterizing factors contributing to the emergence and the dissemination of antibiotic resistance clones in the hospital and in the community. Our research projects focus on Enterobacteriaceae resistant to carbapenems and/or expressing extended spectrum b-lactamases. The Unit is located at the Institut Pasteur and at the Bicêtre Hospital, and is a joint structure between the Institut Pasteur, the Assistance Public Hôpitaux de Paris (APHP) and the University Paris Sud. Establishing a link between research and clinical cases is a key focus of our research.

Our research in the Unit is  focused on mycobacterial research on these pathogenic  species, with main focus on mycobacterial type VII / ESX secretion systems, the patho-evolution of  the Mycobacterium tuberculosis complex – starting from a pool of Mycobacteriium canettii-like generic mycobacteria, as well as on selected aspects of mycobacterial pathogenicity, anti-mycobacterial immunity and anti-tuberculosis vaccine development.

In our group we use cutting-edge phylogenomics approaches to study the macroevolutionary processes that led to the current diversity of microorganisms, with an original view on the whole Tree of Life. We are particularly interested in resolving the global phylogenies of both Bacteria and Archaea, reconstructing the evolutionary relationships among the three domains of Life, and highlighting the existence of novel and important microbial clades. These robust phylogenetic frames are essential to reconstruct the diversity and evolutionary history of key microbial cellular processes, with an important component of functional annotation and gene discovery, which drives experimental work. Together, our researches allow us to address major evolutionary transitions in the history of life, and to challenge established paradigms in ancient microbial evolution.

Our lab is interested in the diversity, evolution and epidemiology of bacterial pathogens and in the links between the genotypic and phenotypic (ecology, colonization, transmission, virulence, antibiotic resistance, immune response) diversity of the strains within particular species. We focus on three pathogens of high public health importance: the multidrug resistant Klebsiella pneumoniae, which causes various types of infections including urinary tract, respiratory and blood infections; Bordetella pertussis, the agent of whooping cough; and Corynebacterium diphtheriae, the agent of diphtheria. We combine epidemiological surveillance, microbiology, genomics, proteomics, bioinformatics and immunological approaches as well as in-vivo and in-vitro models of infection. We also develop and maintain genomic libraries of bacterial genotypes and strain nomenclatures that facilitate global collaborative surveillance and population biology of bacterial pathogens.