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.