Welcome on the Necker-Enfants Malades Institute website

Understand how bacterial stress can shape and permanently disrupt the stability of the genome and epigenome

from basic science:
to the translational research:
Laurence Arbibe
Genome plasticity and infections

Laurence Arbibe is an INSERM director and a team leader at the INEM since 2014. After a residency in Intensive Care and Anesthesiology, a PhD on the biochemistry of phospholipase A2 (Institut Pasteur, L. Touqui team) and a postdoc in immunology at the Scripps Research Institute (R. Ulevitch lab), she obtained an academic position at the INSERM in P. Sansonetti Lab (Institut Pasteur). She dedicated her career to research and focused on signal transduction pathways driving the innate immune response (Arbibe et al, Nature Immunol, 2000). LA has provided pioneering data showing that a bacterial effector can target epigenetic information carried by host promoter chromatin and thereby takes over the control of a small number of immune genes (Arbibe et al, Nature Immunol 2007). Using bacterial proteins as probes to identify new mechanisms controlling the immune epigenome, the group has accumulated expertise in the field of chromatin regulation of innate immune gene expression. The research is now focused on the mechanisms by which bacterial stress imposed by commensal or pathogenic bacteria can shape chromatin information and eventually destabilize the epigenome and genome in the gut.

Focus

  • Unraveling epigenetic regulators sustaining tolerance in the gut and exploring their therapeutic potential in Inflammatory Bowel Diseases.
  • Identifying bacterial mechanisms promoting genomic instability in the gut, with a focus on genotoxins released by enterobacteria.

Introduction

Tolerance is a host defense strategy by which a tissue can protect against immune–inflammatory stressors. With the constant assault of antigens and resident microbes, the gut is by essence submitted to environmental stresses. Control of inflammation and tissue repair capacity are equally central for gut tolerance. Epigenetics captures environmental stresses and translate them into specific gene expression patterns. However, little is known on the mechanisms by which gut tolerance is epigenetically regulated and how those mechanisms nurture inflammatory states seen in Inflammatory Bowel Diseases (IBD). Thus, identifying epigenetic regulators sustaining tolerance is mandatory for understanding IBD pathogenesis and should lead to novel therapeutic strategies.

Inflammation and genomic instability can be prevented under gnotobiotic conditions revealing a link between the commensal flora and intestinal diseases. Genotoxins are a family of microbial effectors in pathogenic and commensal bacteria. So far only three types of bacterial genotoxins are identified. To what extend these effectors act as virulence factors during in vivo infections is unclear. Moreover, whether the carcinogenic effect shown in vitro is relevant in vivo during chronic intoxication remains uncertain. Thus, there is a need for identification of new genotoxins and for development of models exploring their implication in infectious diseases and tumorigenesis.

Research objectives

1- Explore the implication of the chromatin reader HP1 in anti-inflammation and tissue regeneration in the gut

Our studies spotlighted the epigenetic regulator HP1γ as a sensor of acute inflammation in the colon. HP1 is a chromatin-associated transcriptional silencer enriched in heterochromatin, while also silencing inducible genes. HP1 also interacts with Argonautes proteins suggesting functions in small RNA-mediated gene regulation. We showed that HP1 acts as a repressor of inflammatory chemokines while promoting genes involved in stem cell renewal and tissue repair. We will:
- decrypt the functions of HP1 in small RNA-mediated gene regulation
- unravel its functions in anti-inflammation and intestinal regeneration
- develop innovative approaches reinforcing HP1 bioactivity in the intestine

2- Identify genotoxins and explore their implication in infectious diseases and genomic instability

We have shown that some enteropathogens such as Shigella flexneri can inactivate the tumor suppressor gene p53 in the context of genotoxic stress to preserve the life of its own epithelial niche. This example illustrates a mechanism by which bacteria can potentially induce genomic instability. In this context, the identification of bacterial traits that can directly alter the host genome is crucial to understanding how some bacterial species promote cancer.

Our second line of research aims:
- to the identification of new bacterial genotoxins released by both commensal and pathogenic enterobacteria.
- to modelize the long-term impact of this genotoxic stress on the stability of the host genome and epigenome.

Main publications

  • Threonine eliminylation by bacterial phosphothreonine lyases rapidly causes crosslinking of MAPK in live cells
    Meijer BM, Jang S, Guerrera IC, Chhuon C, Lipecka J, Baleux F, Sansonetti PJ, Muchardt C, Arbibe L
    (2017) J Biol Chem, accepted
  • Targeting of chromatin readers: a novel strategy used by the Shigella flexneri virulence effector OspF to reprogram transcription.
    Habiba H, Rachez C, Meijer BM, Muchardt C and Arbibe L
    (2015) Microbial Cell 2: 1 - 32
  • Shigella flexneri targets the HP1γ subcode through the phosphothreonine lyase OspF.
    Harouz H, Rachez C, Meijer BM, Marteyn B, Donnadieu F, Cammas F, Muchardt C, Sansonetti PJ , Arbibe L
    (2014) EMBO J 22 : 2606-2622
  • Calpain Activation by the Shigella flexneri Effector VirA Regulates Key Steps in the Formation and Life of the Bacterium’s Epithelial Niche.
    Bergounioux J, Elisee R, Prunier AL, Donnadieu F, Sperandio B, Sansonetti PJ and Arbibe L
    (2012) Cell Host Microbe 11, 240–252
Last 30 publications

2014

  • Harouz H, Rachez C, Meijer BM, Marteyn B, Donnadieu F, Cammas F, Muchardt C, Sansonetti P, Arbibe L.Shigella flexneri targets the HP1γ subcode through the phosphothreonine lyase OspF. EMBO J. 2014 Nov 18;33(22):2606-22.
  • 2012

  • Bergounioux J, Arbibe L. [Calpain activation by Shigella flexneri regulates key steps in the life and death of bacterium's epithelial niche]. Med Sci (Paris). 2012 Dec;28(12):1029-31.
  • Bergounioux J, Elisee R, Prunier AL, Donnadieu F, Sperandio B, Sansonetti P, Arbibe L. Calpain activation by the Shigella flexneri effector VirA regulates key steps in the formation and life of the bacterium's epithelial niche. Cell Host Microbe. 2012 Mar 15;11(3):240-52.
  • ≤ 2010

  • Tran Van Nhieu G, Arbibe L. Genetic reprogramming of host cells by bacterial pathogens. F1000 Biol Rep. 2009 Oct 29;1:80.
  • Arbibe L. Immune subversion by chromatin manipulation: a 'new face' of host-bacterial pathogen interaction. Cell Microbiol. 2008 Aug;10(8):1582-90.
  • Mazurkiewicz P, Thomas J, Thompson JA, Liu M, Arbibe L, Sansonetti P, Holden DW. SpvC is a Salmonella effector with phosphothreonine lyase activity on host mitogen-activated protein kinases. Mol Microbiol. 2008 Mar;67(6):1371-83.
  • Arbibe L, Sansonetti PJ. Epigenetic regulation of host response to LPS: causing tolerance while avoiding Toll errancy. Cell Host Microbe. 2007 Jun 14;1(4):244-6.
  • Arbibe L, Sansonetti P. [Shigella flexneri modulates host cell epigenetic information as a strategy to shape the transcriptional response]. Med Sci (Paris). 2007 Mar;23(3):238-40.
  • Arbibe L, Kim DW, Batsche E, Pedron T, Mateescu B, Muchardt C, Parsot C, Sansonetti PJ. An injected bacterial effector targets chromatin access for transcription factor NF-kappaB to alter transcription of host genes involved in immune responses. Nat Immunol. 2007 Jan;8(1):47-56.
  • Kaltschmidt B, Ndiaye D, Korte M, Pothion S, Arbibe L, Prüllage M, Pfeiffer J, Lindecke A, Staiger V, Israël A, Kaltschmidt C, Mémet S. NF-kappaB regulates spatial memory formation and synaptic plasticity through protein kinase A/CREB signaling. Mol Cell Biol. 2006 Apr;26(8):2936-46.
  • Pendaries C, Tronchère H, Arbibe L, Mounier J, Gozani O, Cantley L, Fry MJ, Gaits-Iacovoni F, Sansonetti PJ, Payrastre B. PtdIns5P activates the host cell PI3-kinase/Akt pathway during Shigella flexneri infection. EMBO J. 2006 Mar 8;25(5):1024-34.
  • Arbibe L, Mira JP, Teusch N, Kline L, Guha M, Mackman N, Godowski PJ, Ulevitch RJ, Knaus UG. Toll-like receptor 2-mediated NF-kappa B activation requires a Rac1-dependent pathway. Nat Immunol. 2000 Dec;1(6):533-40.
  • Mira JP, Cariou A, Grall F, Delclaux C, Losser MR, Heshmati F, Cheval C, Monchi M, Teboul JL, Riché F, Leleu G, Arbibe L, Mignon A, Delpech M, Dhainaut JF. Association of TNF2, a TNF-alpha promoter polymorphism, with septic shock susceptibility and mortality: a multicenter study. JAMA. 1999 Aug 11;282(6):561-8.
  • Touqui L, Arbibe L. A role for phospholipase A2 in ARDS pathogenesis. Mol Med Today. 1999 Jun;5(6):244-9.
  • Berger A, Havet N, Vial D, Arbibe L, Dumarey C, Watson ML, Touqui L. Dioleylphosphatidylglycerol inhibits the expression of type II phospholipase A2 in macrophages. Am J Respir Crit Care Med. 1999 Feb;159(2):613-8.
  • Arbibe L, Koumanov K, Vial D, Rougeot C, Faure G, Havet N, Longacre S, Vargaftig BB, Béréziat G, Voelker DR, Wolf C, Touqui L. Generation of lyso-phospholipids from surfactant in acute lung injury is mediated by type-II phospholipase A2 and inhibited by a direct surfactant protein A-phospholipase A2 protein interaction. J Clin Invest. 1998 Sep 15;102(6):1152-60.
  • Vial D, Arbibe L, Havet N, Dumarey C, Vargaftig B, Touqui L. Down-regulation by prostaglandins of type-II phospholipase A2 expression in guinea-pig alveolar macrophages: a possible involvement of cAMP. Biochem J. 1998 Feb 15;330 ( Pt 1):89-94.
  • Arbibe L, Vial D, Rosinski-Chupin I, Havet N, Huerre M, Vargaftig BB, Touqui L. Endotoxin induces expression of type II phospholipase A2 in macrophages during acute lung injury in guinea pigs: involvement of TNF-alpha in lipopolysaccharide-induced type II phospholipase A2 synthesis. J Immunol. 1997 Jul 1;159(1):391-400.
  • Permanent researcher
    Laurence Arbibe
    Researcher
    +33 (0)1 72 60 64 30
    Permanent engineer
    Elisabeth Ageron-Ardila
    Technician
    +33 (0)1 72 60 64 31
    Post-doctoral degree
    Jorge Mata Garrido
    Post-Doctoral Researcher
    +33(0)172 60 64 31
    PhD
    Xiangyan He
    PhD Student
    +33(0)1 72 60 64 31
    Caroline Reisacher
    PhD Student
    +33(0)172 60 64 31
    Address

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    Support(s)
    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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