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Understanding the mechanisms by which bacteria disseminate in the host beyond the port-of-entry

from basic science:
  • bacteria
  • pathogenesis
to the translational research:
  • anti-infective
  • vaccine
  • diagnostic
Xavier Nassif
Alain Charbit
Pathogenesis of systemic infections

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

Two complementary approaches 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, using two model organisms. (i) Francisella tularensis, a Gram-negative facultative intracellular bacterium, causative agent of the zoonotic disease tularemia. The virulence of this pathogen is linked to its capacity to multiply in the cytosolic compartment of infected macrophages. (ii) Staphylococcus aureus, a Gram-positive pathogen initially classified as strict extracellular bacterium, is now considered as a non-classical facultative intracellular pathogen and its intracellular life style is associated with persistence and relapse. Our objectives are to understand how the metabolism of these bacteria has evolved to adapt to their intracellular niche(s), and to define, at the single cell level, how the metabolism of the host itself is modified in response to the infection.

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.
Last 30 publications

2017

  • MAÏSSA N, COVARELLI V, JANEL S, DUREL B, SIMPSON N, BERNARD SC, PARDO-LOPEZ L, BOUZINBA-SEGARD H, FAURE C, SCOTT MGH, COUREUIL M, MORAND PC, LAFONT F, NASSIF X, MARULLO S, BOURDOULOUS S. Strength of Neisseria meningitidis binding to endothelial cells requires highly-ordered CD147/β2-adrenoceptor clusters assembled by alpha-actinin-4. Nat Commun. 8:15764.
  • GUET-REVILLET H, TOMINI E, EMIRIAN A, JOIN-LAMBERT O, LECUYER H, ZAHAR JR, JULLIEN V. Piperacillin/tazobactam as an alternative antibiotic therapy to carbapenems in the treatment of urinary tract infections due to extended-spectrum β-lactamase-producing Enterobacteriaceae: an in silico pharmacokinetic study. Int J Antimicrob Agents. 49(1):62-66.
  • PARIZE P, MUTH E, RICHAUD C, GRATIGNY M, PILMIS B, LAMAMY A, MAINARDI JL, CHEVAL J, DE VISSER L, JAGOREL F, BEN YAHIA L, BAMBA G, DUBOIS M, JOIN-LAMBERT O, LERUEZ-VILLE M, NASSIF X, LEFORT A, LANTERNIER F, SUAREZ F, LORTHOLARY O, LECUIT  M, ELOIT M. Untargeted next-generation sequencing-based first-line diagnosis of infection in immuno-compromised adults: a multicentre, blinded, prospective study. Clin Microbiol Infect. pii: S1198-743X(17)30094-0.
  • CHARLIER C, PERRODEAU E, LECLERCQ A, CAZENAVE B, PILMIS B, HENRY B, LOPES A, MAURY MM, MOURA A, GOFFINET F, DIEYE HB, THOUVENOT P, UNGEHEUER MN, TOURDJMAN M,  GOULET V, DE VALK H, LORTHOLARY O, RAVAUD P, LECUIT M; MONALISA study group. Clinical features and prognostic factors of listeriosis: the MONALISA national prospective cohort study. Lancet Infect Dis. pii: S1473-3099(16)30521-7.
  • LECUYER H, BORGEL D, NASSIF X, COUREUIL M. Pathogenesis of meningococcal purpura fulminans. Pathog Dis. 1;75(3).
  • GUET-REVILLET H, JAIS JP, UNGEHEUER MN, COIGNARD-BIEHLER H, DUCHATELET S, DELAGE M, LAM T, HOVNANIAN A, LORTHOLARY O, NASSIF X, NASSIF A, JOIN-LAMBERT O. The microbiological landscape of anaerobic infections in Hidradenitis Suppurativa: a prospective metagenomic study. Clin Infect Dis. doi:10.1093/cid/cix285.
  • BILLE E, MEYER J, JAMET A, EUPHRASIE D, BARNIER JP, BRISSAC T, LARSEN A, PELISSIER P, NASSIF X. A virulence-associated filamentous bacteriophage of Neisseria meningitidis increases host-cell colonisation. PLoS Pathogens. 13(7): e1006495. 
  • JAMET A, TOUCHON M, RIBEIRO-GONÇALVES B, CARRIÇO J, CHARBIT A, NASSIF X, RAMIREZ M, ROCHA E. A widespread family of polymorphic toxins carried by temperate phages. BMC Biology. Aug 29;15(1):75. 
  • ROLLIN G, TAN X, TROS F, DUPUIS M, Nassif X, CHARBIT A, COUREUIL M. Intracellular survival of Staphylococcus aureus in endothelial cells: a matter of growth or persistence. Front. Microbiol. 8 :1354.
  • GHENASSI A, GROSS DA, LORAIN S, TROS F, URBAIN D, BENKHELIFA-ZIYYAT S, CHARBIT A, DAVOUST J, CHAPPERT P. Intradermal immunization with rAAV1 vector induces robust memory CD8+ T cellresponses independently of transgene expression in dendritic cells. Mol Ther. Jul 15. pii: S1525-0016(17)30282-4.
  • ZIVERI J, TROS F, GUERRERA IC, CHHUON C, AUDRY M, DUPUIS M, BAREL M, KORNIOTIS S, FILLATREAU S, GALES L, CAHOREAU E, CHARBIT A. Fructose-1,6-bisphosphate aldolase, a ubiquitous metabolic enzyme with regulatory functions in pathogenic Francisella. Nat Commun. 8(1):853.
  • ASCHARD H, TOBIN M, HANCOCK D, SKURNIK D, AKSHAY S, JAMES A, SMITH A, MANICHAIKUL A, LOTH D, STRACHAN D, O’CONNOR G, BARR G, BRUSSELLE G, HALL I, KAPRIO J, WILSON J, WILK J, HUA ZHAO J, DE JONG K, WAIN L, ARTIGAS M, BOEZEN H, JARVELIN M, FORNAGE M, CASSANO P, GHARIB S, HECKBERT S, GUDNASON V, RAWAL R, SCHULZ H, TANG W, DUPUIS J, JOSHI A, LONDON S, KRAFT P. Evidence for Large-Scale Gene-by-Smoking Interaction Effects on Pulmonary Function. Int J Epidemiol. 46 (3):894-904.
  • ROUX D, WEATHERHOLT M, CLARK B, GADJEVA M, RENAUD D, SCOTT D, SKURNIK D, PRIEBE G, PIER GB, GERARD C AND YODER-HIMES D. Immune Recognition of the Epidemic Cystic Fibrosis Pathogen Burkholderia dolosa. Infect. Immun. 85(6). pii: e00765-16
  • ASCHARD H, GUILLEMOT V, VILHJALMSSON B, PATEL C, SKURNIK D, YE J, WOLPIN B, KRAFT P, ZAITLEN N.  Covariate Selection for Association Screening in Multi-Phenotype Genetic studies. Nat Genet. 49(12):1789-1795.
  • 2016

  • KOLAPPAN S, COUREUIL M, YU X, NASSIF X, EGELMAN EH, CRAIG L. Structure of the  Neisseria meningitidis Type IV pilus. Nat Commun. 4;7:13015.
  • TOUBIANA J, TIMSIT S, FERRONI A, GRASSEAU M, NASSIF X, LORTHOLARY O, ZAHAR JR, CHALUMEAU M. Community-Onset Extended-Spectrum β-Lactamase-Producing Enterobacteriaceae Invasive Infections in Children in a University Hospital in France. Medicine (Baltimore). 95(12):e3163.
  • CAPEL E, ZOMER AL, NUSSBAUMER T, BOLE C, IZAC B, FRAPY E, MEYER J, BOUZINBA-SEGARD H, BILLE E, JAMET A, CAVAU A, LETOURNEUR F, BOURDOULOUS S, RATTEI T, NASSIF X, COUREUIL M. Comprehensive Identification of Meningococcal Genes and  Small Noncoding RNAs Required for Host Cell Colonization. MBio. 2;7(4).
  • BERGOUNIOUX J, COUREUIL M, BELLI E, LY M, CAMBILLAU M, GOUDIN N, NASSIF X, JOIN-LAMBERT O. Experimental Evidence of Bacterial Colonization of Human Coronary Microvasculature and Myocardial Tissue during Meningococcemia. Infect Immun. 84(10):3017-23.
  • MEYER J, BRISSAC T, FRAPY E, OMER H, EUPHRASIE D, BONAVITA A, NASSIF X, BILLE  E. Characterization of MDAΦ, a temperate filamentous bacteriophage of Neisseria meningitidis. Microbiology. 162(2):268-82.
  • BAREL M, HARDUIN-LEPERS  A, PORTIER L, SLOMIANNY MC, CHARBIT A. Host glycosylation pathways and the unfolded protein response, new players in the infection by Francisella. Cell Microbiol. 18(12):1763-1781. 
  • RIGARD M, BRÖMS JE,  MOSNIER A, MARTIN A, PUNGINELLI C, CHARBIT A, TELOUK P, WAYNE C, TERRADOT L, SJÖSTEDT A, HENRY T. Francisella tularensis IglG belongs to a novel family of PAAR-like T6SS proteins and harbors a unique N-terminal extension required for virulence. PLoS Pathogens 12(9):e1005821.
  • ROUX D, PONS S, GUILLARD T, RICARD JD, PIER GB, SKURNIK D. Impact of drug resistance on virulence and fitness of bacterial pathogens. Crit Care Med. 44(1):e50-1.
  • SKURNIK D, CLERMONT O, GUILLARD T, LAUNAY A, DANILCHANKA O, PONS S, DIANCOURT L, LEBRETON F, KADLEC K, ROUX D, JIANG D, DION S, ACHARD H, DENAMUR M, CYWES-BENTLEY C, SCHWARZ S, TENAILLON O, ANDREMONT A, PICARD B, MEKALANOS J, BRISSE S, DENAMUR E. Emergence of Antimicrobial Resistant Escherichia coli of Animal Origin Spreading in Humans. Mol Bio Evol. 33(4):898-914.
  • SKURNIK D, ROUX D, PONS S, GUILLARD T, LU X, CYWES-BENTLEY C, PIER GB. Extended spectrum antibodies protective against carbapenemase producing Enterobacteriaceae. J Antimicrob Chemother. 71(4):927-35.
  • SOKOL H, LEDUCQ V, ASCHARD H, JEGOU S, LANDMAN C, GIUSEPPINA L, COSNES J, SEKSIK P, LANGELLA P, SKURNIK D, RICHARD ML, BEAUGERIE L. Fungal Microbiota Dysbiosis in Inflammatory Bowel Disease. Gut. pii: gutjnl-2015-310746.
  • SKURNIK D, CYWES-BENTLEY C, PIER GB. The exceptionally broad-based potential of active and passive vaccination targeting the conserved microbial surface polysaccharide PNAG. Expert Rev Vaccines. 15(8):1041-53.
  • GUILLARD T, PONS S, ROUX D, PIER GB, SKURNIK D. Antibiotic resistance and virulence: Understanding the link and its consequences for prophylaxis and therapy. Bioessays. 38(7):682-93.
  • 2015

  • JAMET A, NASSIF X. Characterization of the Maf family of polymorphic toxins in pathogenic Neisseria species. Microb Cell. 2(3):88-90.
  • ZAHAR JR, POIREL L, DUPONT C, FORTINEAU N, NASSIF X, NORDMANN P. About the usefulness of contact precautions for carriers of extended-spectrum beta-lactamase-producing Escherichia coli. BMC Infect Dis. 12;15:512.
  • JOIN-LAMBERT O, DUCHATELET S, DELAGE M, MISKINYTE S, COIGNARD H, LEMARCHAND N, ALEMY-CARREAU M, LORTHOLARY O, NASSIF X, HOVNANIAN A, NASSIF A. Remission of refractory pyoderma gangrenosum, severe acne, and hidradenitis suppurativa (PASH) syndrome using targeted antibiotic therapy in 4 patients. J Am Acad Dermatol. 73(5 Suppl 1):S66-9.
  • DELAGE M, GUET-REVILLET H, DUCHATELET S, HOVNANIAN A, NASSIF X, NASSIF A, JOIN-LAMBERT O. Deciphering the microbiology of hidradenitis suppurativa: a step  forward towards understanding an enigmatic inflammatory skin disease. Exp Dermatol. 24(10):736-7.
  • JAMET A, JOUSSET AB, EUPHRASIE D, MUKORAKO P, BOUCHARLAT A, DUCOUSSO A, CHARBIT A, NASSIF X. A new family of secreted toxins in pathogenic Neisseria species. PLoS Pathog. 11(1):e1004592.
  • Gesbert G, Ramond E, TROS F, DAIROU J, Frapy E, Barel M, Charbit A. Importance of branched-chain amino acid utilization in Francisella intracellular adaptation. Infect. Immun. 83 (1): 173-183.
  • RAMOND E, GESBERT G, GUERRERA IC, CHHUON C, DUPUIS M, RIGARD M, HENRY T, BAREL M, CHARBIT A. Importance of host cell arginine uptake in Francisella phagosomal escape and ribosomal protein amounts. Mol Cell Proteomics. (4):870-81. 
  • RENIER S, CHAFSEY I, CHAMBON C, CHARBIT A,  HÉBRAUD M, DESVAUX M. Contribution of the multiple Type I signal peptidases to the secretome of Listeria monocytogenes: Deciphering protein substrate specificity by exoproteomic analysis. J. Proteomics. pii: S1874-3919(15)00015-9. 
  • BRISSAC T, ZIVERI J, RAMOND E, TROS F, KOCK S, DUPUIS M, BRILLET M, BAREL M, PEYRIGA L, CAHOREAU E, CHARBIT A. Gluconeogenesis, an essential metabolic pathway for pathogenic Francisella. Mol Microbiol. 98 (3) : 403–604.
  • ROUX D, CYWES-BENTLEY C, ZHANG YI-FAN, PONS S, KEARNS D, LITTLE DJ, HOWELL PL, PIER GB* AND SKURNIK D*. Identification of poly-N-acetylglucosamine as a major polysaccharide component of the Bacillus subtilis biofilm matrix. J Biol Chem. 290(31):19261-72. * Equally contributed to this work
  • ROUX D*, DANILCHANKA O*, GUILLARD T, CATTOIR V, ASCHARD H, FU Y, ANGOULVANT F, MESSIKA J, RICARD J-D, MEKALANOS J, LORY S, PIER GB AND SKURNIK D. Fitness cost of antibiotic susceptibility during infection. Sci Transl Med. 7(297):297ra114. * Equally contributed to this work.
  • Permanent researcher
    Jean Bergounioux
    Professor Researcher
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    Emmanuelle Bille
    -
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    Alain Charbit
    Researcher
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    Mathieu Coureuil
    Researcher
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    Mohamed El Behi
    Researcher
    Anne Jamet
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    Hervé Lécuyer
    Professor Researcher
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    Xavier Nassif
    Professor Researcher
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    David Skurnik
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    HRH Princess Caroline of Hanover, who through the Princess Grace Foundation, already supports medical research and anything that helps to relieve the sick children in France and around the world, has agreed to commit to our side so that our Center of Molecular medicine continues to meet the current challenges and fight diseases, and in particular the ones affecting children.

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