Streptococcus gallolyticus subsp. gallolyticus (Sgg) is implicated in life-threatening bacteremia, infective endocarditis (IE) and colorectal cancer (CRC). Despite its clinical importance, the underlying virulence mechanism of Sgg is poorly understood. A prominent feature of Sgg IE or bacteremia is the well-documented high rate of comorbidity with CRC, averaging around ~60% of cases. This underscores a strong connection between Sgg activities in the intestinal tract and Sgg infection in the circulatory system. Work from our lab and others have sort to understand the detailed interactions between Sgg and the colonic epithelium and how the interactions lead to pathological changes and diseases. Studies have found that Sgg is able to stimulate colon cancer cell proliferation and translocate across an epithelial barrier in a paracellular fashion. In pre-clinical models, Sgg has been shown to “drive” the development of colon tumors. The specific Sgg factors and host pathways underlying these pathogenic activities, however, are largely unknown. Recent findings from our lab demonstrated that a type VII secretion system (T7SS) plays a significant role in Sgg virulence. In preliminary studies to further dissect the activities mediated by the T7SS, a specific T7SS effector, EsxA, was found to be crucial in influencing colonic epithelial homeostasis. Moreover, preliminary data suggests that EsxA functions by acting as a novel ligand for a host cell surface growth factor receptor of critical function and holds great promise as a key virulence factor mediating multiple pathogenic phenotypes of Sgg. To the best of our knowledge, these findings highlight a novel virulence mechanism for Sgg and provide the first experimental evidence for T7SS regulation of a growth factor receptor. The goal of this proposal is to further delineate the importance of EsxA in Sgg virulence and to elucidate the signaling and biological outcomes induced by EsxA, using in vitro cell cultures and animal models well established in our lab. The broad applicability of the proposed virulence mechanism in Sgg strains will also be determined. Successful completion of the proposed studies will fill major knowledge gaps in Sgg virulence and advance a new understanding of T7SS function and microbial regulation of growth factor receptors.