Molecular determinants of the interactions between Segmented Filamentous Bacterium and the gut epithelium

par Iris Nkamba

Projet de thèse en Immunologie

Sous la direction de Nadine Cerf-bensussan.

Thèses en préparation à Sorbonne Paris Cité , dans le cadre de 562 Bio Sorbonne Paris Cité , en partenariat avec IHU Imagine-Institut des Maladies Génétiques (equipe de recherche) depuis le 20-07-2016 .


  • Résumé

    During their long coevolution, intestinal bacteria and their hosts have established mutualistic interactions that are controlled through a dialogue with the host immune system. In mammals, the development of the immune system is initiated before birth by a genetic program. Yet, its full development occurs only after birth in response to microbe-derived stimuli. Such stimuli activate epithelial cells and induce the recruitment and activation of multiple hematopoietic cell subsets. As a result, an efficient intestinal barrier is built, resident bacteria can be maintained within the intestinal lumen and intestinal colonisation by pathogens can be prevented or limited.Unexpectedly efficient post-natal maturation of the gut immune barrier depends on a restricted number of species and the laboratory has identified one such key species, a Clostridium-related bacterium called Segmented Filamentous Bacterium (SFB) that plays a critical role and is necessary to establish a balanced immune environment in the gut. SFB is a highly unusual bacterium that intimately attaches to intestinal epithelial cells and colonizes the host just after weaning. Past work, including ours, showed that SFB can induce the maturation of Peyer’s patches and cryptopatch-derived lymphoid follicles, the de novo development of tertiary lymphoid tissue, a strong IgA response, the upregulation of innate defences and an overall healthy immune cell composition that protects the host from pathogens. Notably, SFB is a strong inducer of IL-22 from ILC3s and the only gut commensal in mice that potently induces Th17 cells. Of note, the strong immunostimulatory activity of SFB affects not only the immunological milieu in the intestine but also influences the immune system outside of the gut, thereby contributing to, for example, bone marrow output of myeloid cells, and systemic immune reactivity. Contrary to the role of SFB in modulating the immune system, little is known about the intimate interaction of SFB with epithelial cells as SFB has resisted in vitro culturing for over 50 years. Yet, there is growing evidence that SFB intimate contact with epithelial cells is central to its immunostimulatory effect. Moreover, we recently succeeded in culturing SFB in an SFB-host cell co-culturing system in vitro. This breakthrough now allows the characterization of the host-SFB interaction at a cellular and molecular level. The PhD project therefore involves using the in vitro culture technique of SFB for the identification of critical host and bacterial factors involved in this unusual symbiotic relationship.


  • Résumé

    During their long coevolution, intestinal bacteria and their hosts have established mutualistic interactions that are controlled through a dialogue with the host immune system. In mammals, the development of the immune system is initiated before birth by a genetic program. Yet, its full development occurs only after birth in response to microbe-derived stimuli. Such stimuli activate epithelial cells and induce the recruitment and activation of multiple hematopoietic cell subsets. As a result, an efficient intestinal barrier is built, resident bacteria can be maintained within the intestinal lumen and intestinal colonisation by pathogens can be prevented or limited.Unexpectedly efficient post-natal maturation of the gut immune barrier depends on a restricted number of species and the laboratory has identified one such key species, a Clostridium-related bacterium called Segmented Filamentous Bacterium (SFB) that plays a critical role and is necessary to establish a balanced immune environment in the gut. SFB is a highly unusual bacterium that intimately attaches to intestinal epithelial cells and colonizes the host just after weaning. Past work, including ours, showed that SFB can induce the maturation of Peyer’s patches and cryptopatch-derived lymphoid follicles, the de novo development of tertiary lymphoid tissue, a strong IgA response, the upregulation of innate defences and an overall healthy immune cell composition that protects the host from pathogens. Notably, SFB is a strong inducer of IL-22 from ILC3s and the only gut commensal in mice that potently induces Th17 cells. Of note, the strong immunostimulatory activity of SFB affects not only the immunological milieu in the intestine but also influences the immune system outside of the gut, thereby contributing to, for example, bone marrow output of myeloid cells, and systemic immune reactivity. Contrary to the role of SFB in modulating the immune system, little is known about the intimate interaction of SFB with epithelial cells as SFB has resisted in vitro culturing for over 50 years. Yet, there is growing evidence that SFB intimate contact with epithelial cells is central to its immunostimulatory effect. Moreover, we recently succeeded in culturing SFB in an SFB-host cell co-culturing system in vitro. This breakthrough now allows the characterization of the host-SFB interaction at a cellular and molecular level. The PhD project therefore involves using the in vitro culture technique of SFB for the identification of critical host and bacterial factors involved in this unusual symbiotic relationship.