Welcome on the Necker-Enfants Malades Institute website
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.
