PROJECT SUMMARY Fusobacterium nucleatum, a Gram-negative anaerobe that plays a key role in the development of oral biofilms, or dental plaque, has the remarkable ability to escape host immunity and spread to extraoral sites, including placenta and colon, where it is associated with significant diseases such as preterm birth and colorectal cancer. To date, we have a poor understanding of the mechanisms of virulence and disease by F. nucleatum, and the environmental factors in the extraoral sites that potentially affect the virulence potential of this pathogen. Considering that ethanolamine (EA) – an important source of carbon/nitrogen and energy, and a signaling molecule for some bacterial pathogens – is abundant in placenta during fetal development, we aim to test the central hypothesis that regulated EA metabolism via a specialized organelle, bacterial microcompartment (BMC), modulates the virulence potential of F. nucleatum. This hypothesis is based on our compelling preliminary data showing that environmental EA stimulates BMC formation and expression of EA utilization genes, and that blockage in EA catabolism alters the pathogenicity of F. nucleatum. The major goal of this application is to examine how BMC-mediated EA utilization affects fusobacterial virulence (Aim 1) and how blockage in EA catabolism modulates fusobacterial pathogenicity (Aim 2). The results generated from our studies will not only provide important knowledge regarding the pathophysiology of F. nucleatum and promising therapeutic targets, but also have potential to advance the broad field of host-pathogen interactions.