Decoding the molecular mediators and consequences of host-microbe interactions in inflammatory bowel diseases

About This Grant

PROJECT SUMMARY Microbes and their hosts have co-evolved an extensive interaction interface, and these interactions can be used as a tool to help illuminate fundamental biology of both the microbe and the host. The microbiome has been extensively described in both health and disease, and there are many strains that are associated with particular disease states. Ruminococcus gnavus is a commensal bacteria in the human microbiota, which has consistently been found to be associated with inflammatory bowel disease. The interplay between microbiota and host via small molecule metabolites has been extensively studied, however, in homeostasis, members of the microbiota are restricted to the lumen of the gut, meaning they are physically excluded from making direct contact with host cells. Inflammatory bowel diseases represent a particularly interesting lens through which to investigate direct interaction between bacteria and the host, as breakdown of the barrier can allow direct access to host tissues. Recently, R. gnavus was identified to have several specific interactions with host proteins, including immunoglobulins, the co-stimulatory molecule CD7, and the mucus components trefoil tactors (TFFs). This confluence of a gut commensal associated with IBD that possesses several surface features that directly target host proteins makes it an ideal example to investigate the direct interaction interface between host and microbiota member. These studies will interrogate strain-level differences of a commensal bacteria and illuminate how particular features allow it to occupy host niches and influence the immune environment. This will also provide a framework for interrogating protein-protein interactions at the host-commensal interface. These studies will provide a fundamental understanding of how microbes may influence human immune states in the gut and mechanisms of how the microbiota may drive inflammation in patients with inflammatory bowel disease. The principal investigator is a postdoctoral fellow in the Dept. of Immunobiology at Yale School of Medicine with a background in structural biology and biochemistry. The K99 phase of this award will provide training in mucosal immunology in gnotobiotic mouse models, which will enable the R00 phase of this award and launch an independent research program using interdisciplinary approaches to mechanistically study host-microbe interactions.