Xavier Nassif, M.D-PhD. is Professor of Microbiology at the Medical School Paris Descartes. He obtained is Medical Degree in 1987 and a PhD at the Pasteur Institute in 1989. After a postdoctoral fellowship he joined in 1992 the « Faculté de Médecine Paris Descartes » where he is heading the Clinical Microbiology Laboratory and the Institut Necker-Enfants Malades.

Alain Charbit, PhD, is Research Director (DR1) from the CNRS. He obtained a PhD at the Pasteur Institute in 1990. He was recruited by the CNRS in 1997. After 15 years at the Pasteur Institute, he joined in 1998 the « Faculté de Médecine Paris Descartes » where he is currently co-heading team 11 at the Institut Necker-Enfants Malades.

Focus

Bacterial systemic infections remain a public health concern in the developed world, Our long term goal is a better understanding of the pathogenesis of these infections in order to identify new targets for prevention and treatment.

Introduction

Systemic infections are characterized by the ability of infecting pathogens to colonize and to disseminate from their port-of-entry into the bloodstream. Two types of bacterial pathogens disseminate beyond their port-of-entry:

1. the extra cellular pathogens that can survive in the extracellular fluids and have developed attributes that prevent phagocytosis by polymorphonuclear cells and killing by the serum. These bacteria are essentially those responsible for sepsis that remains a life-threatening condition and a major contributor of public health and economic burden in the industrialized world. These pathogens are in direct contact with endothelial cells. Much remain to be understood on the mechanisms and consequences of this bacterial interaction with the capillaries, even though this interaction is a prerequisite for metastatic dissemination (crossing of the blood brain barrier for example).
2. The intracellular pathogens that disseminate in the body using a Trojan horse such as macrophages. The mechanisms by which these latter pathogens resist to the bactericidal Intracellular environment have long been studied. On the other hand, these pathogens often critically rely on acquisition of host-derived nutrients for the development of a successful infection. Since nutrient availability depends on host metabolism and differs depending on localization within tissues and varies over the course of infection, intracellular pathogens have had to adapt their metabolism to these host metabolic rearrangements.

Research objectives

Four main research axes are being pursued.

• The first approach focuses on the mechanisms and consequences of the interaction of extra-cellular bacterial pathogens with endothelial cells using Neisseria meningtidis as paradigm. This pathogen following bloodstream invasion from the nasopharynx establishes a strong interaction with the capillaries. This interaction is associated with the occurrence of meningitis and Purpura fulminans. Our objectives are to provide a coherent picture of meningococcal pathogenesis by dissecting the interaction between meningococci and endothelial cells at the molecular, cellular, and tissular levels.
• The second approach consists in deciphering the molecular bases of the host-pathogen metabolic interplay of an intracellular bacterial pathogen, using Francisella tularensis as a model organism. The virulence of this Gram-negative intracellular bacterium, causative agent of the zoonotic disease tularemia, is tightly linked to its capacity to multiply in the cytosolic compartment of infected macrophages. Our objectives are: i) to understand how the metabolism of this bacteria has evolved to adapt to its intracellular niche; and ii) to define how the metabolism of the host itself is modified in response to the infection.
• The third approach aims at providing new insights on Staphylococcus aureus pathogenesis, which is one of the deadliest bacteria in Western countries. We are particularly committed to the study of virulence factors associated with chronic infections and we have implemented translational research projects involving cohorts of children with chronic S. aureus infections (cystic fibrosis and epidermolysis bullosa). Bacterial adaptation explains why bacteria persist at infected sites despite antibiotic treatment. This project will provide an understanding of the molecular mechanisms of adaptation of S. aureus when subjected to high in vivo selection pressure and the consequences on the host inflammatory response.
  Our two main objectives are: i) to identify genetic mutations modulating toxicity and inflammation, through an unbiased proteogenomic analysis of adapted S. aureus isolates and ii) to study the impact of S. aureus adaptation in vitro and in vivo, with a focus on the host inflammatory response and cytokine secretion.
• The fourth axis is "Genomic approaches to microbial pathogenesis and vaccine development". In developed countries, 20% of the bacterial meningitis in neonates is due to Escherichia coli K1. We use TnSeq to (i) identify and understand the genes and regulatory genetic elements contributing to optimal fitness of E. coli K1 from GI tract colonization, to crossing of the blood brain barrier and, (ii), identify and develop new vaccine candidates via a process we have called TnSeq vaccinology. This approach exploits the TnSeq tool to test the effect of host immunity, induced by vaccination with a broadly-protective immunogen such as antibiotic-killed cells, on selection of strains with Tn-interrupted genes. This approach should impact all types of vaccine antigens, not just proteins, a limitation of current antigen identification systems such as reverse vaccinology.

5 main publications

• Ramond E, et al. (2014) Glutamate utilization couples oxidative stress defense and the tricarboxylic acid cycle in Francisella phagosomal escape. PLoS Pathogens Jan. 10(1):e10003893.
• Bernard SC, et al. (2014) Pathogenic Neisseria meningitidis utilizes CD147 for vascular colonization. Nat Med 20(7):725-731.
• Ramond E, et al. (2015) Importance of host cell arginine uptake in Francisella phagosomal escape and ribosomal protein amounts. Mol Cell Proteomics Jan 23. pii: mcp.M114.044552.
• Jamet A, et al. (2015) A new family of secreted toxins in pathogenic Neisseria species. PLoS Pathogens 11(1):e1004592.
• Kolappan S, et al. (2016) Structure of the Neisseria meningitidis Type IV pilus. Nat Commun 7:13015.

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