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.
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.
IBD involve the inappropriate activation of the gastro-intestinal (GI) immune system in genetically susceptible hosts. The gut microbiota is now clearly identified as a major driving force in the disease. An imbalance in the gut microbiota composition (dysbiosis) in IBD patients has been repeatedly reported. One of the major and most common features of this dysbiosis is an increase of Proteobacteria and particularly of Enterobacteriaceae in IBD patients compared to healthy subjects. These changes in the microbiota composition likely have functional consequences as Enterobacteriaceae have proinflammatory effects whereas some Firmicutes have anti-inflammatory properties. Escherichia coli is a prototypic member of the Enterobacteriaceae family. There are two hypotheses to be explored regarding the increased levels of E. coli in IBD: it could be either a primary event triggering inflammation or a secondary event induced by the inflammatory cascade and further promoting destructive pathology. In any case, understanding and exploring E. coli virulence factors associated with the inflammation found in IBD would fill in gaps in our knowledge about the pathophysiology of the disease and may also uncover new therapeutic targets.
Inflammation caused by bacteria Is present in IBD but is also a major characteristic of bacterial infections. Studying both bacterial and host sides during an infectious process should provide important information to understand bacterial pathogenesis in both sepsis and IBD and may reveal new putative therapeutic targets for an immunotherapeutic approach either passive (monoclonal antibodies), or active (Vaccine development) against to prevent and/or treat these pathologies.
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. We showed that HP1 acts as a repressor of inflammatory chemokines while its function in gut physiology unexplored. Through the development of various mice models conditionally inactivating HP1 in the gut epithelium, our research aims at:
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. Thus, our second line of research aims at:
Adherent-Invasive E. coli (AIEC) are particularly implicated in Crohn’s disease as they are found in the mucosa of more than one third of IBD patients. One of these AIEC strains, LF82, is able to adhere and invade intestinal epithelial cells, replicate within macrophages and promote TNF-alpha production by infected macrophages. Using two E. coli strains: the commensal E. coli MG1655 and E. coli LF82, we intend to conduct a systematic analysis of the role of E. coli genes in an inflammatory gastro-intestinal (GI) tract environment by identifying and studying the genes required to colonize murine GI tracts in steady state and inflammatory conditions, in both conventional and germ-free mice and in different parts of the GI tract: Ileum, Jejunum, Colon, and Cecum.
We use TnSeq to (i) better understand bacterial pathogenesis by identifying and studying the genes and regulatory genetic elements contributing to optimal fitness of bacterial pathogens within its host (E. coli K1 and P. aeruginosa), (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. Thus, our lab is invested in advancing vaccine development from target discovery to efficacy studies in relevant animal models.
Mata-Garrido, J., Chang-Marchand, Y., Cherbuy, C., Batsche, E., Muchardt, C. & Arbibe, L. HP1γ sets the biological age of the intestinal epithelium. bioRxiv 11, 61–22 (2020).
Zhang, Y., Devocelle, A., Souza, L., Foudi, A., Tenreira Bento, S., Desterke, C., Sherrard, R., Ballesta, A., Adam, R., Giron-Michel, J. & Chang, Y. BMAL1 knockdown triggers different colon carcinoma cell fates by altering the delicate equilibrium between AKT/mTOR and P53/P21 pathways. Aging (Albany NY) 12, 8067–8083 (2020).
Angoulvant F, Ouldali N, Yang DD, Filser M, Gajdos V, Rybak A, Guedj R, Soussan-Banini V, Basmaci R, Lefevre-Utile A, Brun-Ney D, Beaujouan L, Skurnik D. COVID-19 pandemic: Impact caused by school closure and national lockdown on pediatric visits and admissions for viral and non-viral infections, a time series analysis. Clin Infect Dis. 2020 Jun 3:ciaa710. doi: 10.1093/cid/ciaa710. Online ahead of print. PMID: 32492117 Free PMC article.
Unexpected lessons from the COVID-19 lockdowns in France: Low impact of school opening on common communicable pediatric airborne diseases.
Skurnik D, Rybak A, Yang DD, Pons S, Guedj R, Levy C, Cohen R, Gajdos V, Vasante L, Ouldali N, Angoulvant F.
Clin Infect Dis. 2020 Dec 29:ciaa1899. doi: 10.1093/cid/ciaa1899. Online ahead of print.
Common pediatric respiratory infectious diseases may serve as an early predictor for SARS-CoV-2 new wave of infections. Yang DD, Ouldali N, Gajdos V, Thomas-Sertillanges R, Vasante L, Skurnik D*, Angoulvant F*. Clin Infect Dis. 2020 Sep 7:ciaa1359. doi: 10.1093/cid/ciaa1359. *Equally contributed to this work
COVID-19 pandemic: Impact caused by school closure and national lockdown on pediatric visits and admissions for viral and non-viral infections, a time series analysis. Angoulvant F, Ouldali N, Yang DD, Filser M, Gajdos V, Rybak A, Guedj R, Soussan-Banini V, Basmaci R, Lefevre-Utile A, Brun-Ney D, Beaujouan L, Skurnik D. Clin Infect Dis. 2020 Jun 3:ciaa710. doi: 10.1093/cid/ciaa710.
COVID-19 pandemic: Impact caused by school closure and national lockdown on pediatric visits and admissions for viral and non-viral infections, a time series analysis François Angoulvant, M.D., Ph.D., Naïm Ouldalu, M.D., David Dawei Yang,M.D., Mathilde Filser, Vincent Gajdos, M.D.,Ph.D. Alexis Rybak,M.D., Romain Guedj,M.D.,Ph.D., Valérie Soussan-Bannini,M.D., Romain Basmaci,M.D.,Ph.D., Alain Lefevre-Utile,M.D, Dominique Brun-Ney,M.D., Laure Beaujouan, David Skurnik,M.D.,Ph.D
Clinical and virological responses to a broad-spectrum human monoclonal antibody in an influenza virus challenge study. Sloan SE, Szretter KJ, Sundaresh B, Narayan KM, Smith P, Skurnik D, Bedard S, Trevejo JM, Oldach D, Shriver Z. Antiviral Res. 2020 Mar 6:104763. doi: 10.1016/j.antiviral.2020.10476
Reisacher, C. & Arbibe, L. Not lost in host translation: The new roles of long noncoding RNAs in infectious diseases. Cell. Microbiol. 21, e13119 (2019)
Connor, M., Arbibe, L. & Hamon, M. Customizing Host Chromatin: a Bacterial Tale. Microbiol Spectr 7, 227–245 (2019)
Aschard H, Laville V, Tchetgen ET, Knights D, Imhann F, Seksik P, Zaitlen N, Silverberg MS, Cosnes J, Weersma RK, Xavier R, Beaugerie L, Skurnik D*, Sokol H*. Genetic effects on the commensal microbiota in inflammatory bowel disease patients. PLoS Genet. 2019 Mar 8;15(3):e1008018. doi: 10.1371/journal.pgen.1008018. eCollection 2019 Mar. PMID: 30849075 Free PMC article. *Equally contributed to this work
Differential Changes in Breath Volatile Metabolites to Identify Carbapenem-Resistant Enterobacteriaceae (CRE) in a Murine Pneumonia Model
Nour Ismail, Hazem Albashash, Mahesh J Thalavitiya Acharige, Mohamad Hejazi, Carmen Leon Astudillo, Obadah Aloum, Seena Koshy, Laura Fredenburgh, Raji Balasubramanian, David Skurnik, Thomas Guillard, Sophia Koo. Open Forum Infect Dis. 2019 Oct; 6(Suppl 2): S722–S723. Published online 2019 Oct 23. doi: 10.1093/ofid/ofz360.1814 PMCID: PMC6809847
Genetic effects on the commensal microbiota in inflammatory bowel disease patients. Aschard H, Laville V, Tchetgen ET, Knights D, Imhann F, Seksik P, Zaitlen N, Silverberg MS, Cosnes J, Weersma RK, Xavier R, Beaugerie L, Skurnik D*, Sokol H*. PLoS Genet. 2019 Mar 8;15(3):e1008018. doi: 10.1371/journal.pgen.1008018. eCollection 2019 *Equally contributed to this work
Zhang, Y., Giacchetti, S., Parouchev, A., Hadadi, E., Li, X., Dallmann, R., Xandri-Monje, H., Portier, L., Adam, R., Lévi, F., Dulong, S. & Chang, Y. Dosing time dependent in vitro pharmacodynamics of Everolimus despite a defective circadian clock. Cell Cycle 17, 33–42 (2018).
Sun, C. H., Wacquier, B., Aguilar, D. I., Carayol, N., Denis, K., Boucherie, S., Valencia-Gallardo, C., Simsek, C., Erneux, C., Lehman, A., Enninga, J., Arbibe, L., Sansonetti, P., Dupont, G., Combettes, L. & Tran Van Nhieu, G. The Shigella type III effector IpgD recodes Ca(2+) signals during invasion of epithelial cells. EMBO J. e201696272 (2017). doi:10.15252/embj.201696272
Meijer, B. M., Jang, S. M., Guerrera, I. C., Chhuon, C., Lipecka, J., Reisacher, C., Baleux, F., Sansonetti, P. J., Muchardt, C. & Arbibe, L. Threonine eliminylation by bacterial phosphothreonine lyases rapidly causes cross-linking of mitogen-activated protein kinase (MAPK) in live cells. J. Biol. Chem. 292, 7784–7794 (2017).
Guillard, T., Pons, S., Roux, D., Pier, G. B. & Skurnik, D. Antibiotic resistance and virulence: Understanding the link and its consequences for prophylaxis and therapy. Bioessays 38, 682–693 (2016).
Roux, D., Pons, S., Guillard, T., Ricard, J.-D., Pier, G. B. & Skurnik, D. Impact of Drug Resistance on Virulence and Fitness of Bacterial Pathogens. Crit Care Med 44, e50–e51 (2016).
Skurnik, D., Clermont, O., Guillard, T., Launay, A., Danilchanka, O., Pons, S., Diancourt, L., Lebreton, F., Kadlec, K., Roux, D., Jiang, D., Dion, S., Aschard, 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 Biol Evol 33, 898–914 (2016).
Roux, D., Danilchanka, O., Guillard, T., Cattoir, V., Aschard, H., Fu, Y., Angoulvant, F., Messika, J., Ricard, J.-D., Mekalanos, J. J., Lory, S., Pier, G. B. & Skurnik, D. Fitness cost of antibiotic susceptibility during bacterial infection. Sci Transl Med 7, 297ra114–297ra114 (2015).
Roux, D., Cywes-Bentley, C., Zhang, Y.-F., Pons, S., Konkol, M., Kearns, D. B., Little, D. J., Howell, P. L., Skurnik, D*. & Pier, G. B*. Identification of Poly-N-acetylglucosamine as a Major Polysaccharide Component of the Bacillus subtilis Biofilm Matrix. J. Biol. Chem. 290, 19261–19272 (2015). *Equally contributed to this work
Harouz, H., Rachez, C., Meijer, B. M., 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. 33, 2606–2622 (2014).
Harouz, H., Rachez, C., Meijer, B., Muchardt, C. & Arbibe, L. Targeting of chromatin readers: a novel strategy used by the Shigella flexneri virulence effector OspF to reprogram transcription. Microb Cell 2, 26–28 (2014).
Lu, X*., Skurnik, D*., Pozzi, C., Roux, D., Cywes-Bentley, C., Ritchie, J. M., Munera, D., Gening, M. L., Tsvetkov, Y. E., Nifantiev, N. E., Waldor, M. K. & Pier, G. B. A Poly-N-acetylglucosamine-Shiga toxin broad-spectrum conjugate vaccine for Shiga toxin-producing Escherichia coli. mBio 5, e00974–14 (2014). *Equally contributed to this work
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.
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.