Type VII secretion in Streptococcus gallolyticus adherence

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Streptococcus gallolyticus subsp. gallolyticus (Sgg) is a medically important gut pathobiont that causes life-threatening bacteremia and infective endocarditis (IE) and promotes colorectal cancer (CRC). However, the molecular mechanisms underlying Sgg pathogenicity remain poorly understood. The pathogenic process of Sgg (previously known as S. bovis biotype I) involves colonizing the colon, influencing the colonic epithelium homeostasis and barrier integrity, and disseminating from the gut to the circulatory system to cause bacteremia and IE. Our long-term goals are to understand how this organism colonizes the colon, how it affects gut epithelial homeostasis and integrity, and how to use the knowledge to mitigate Sgg-induced pathologies. This application will investigate a novel mechanism that mediates Sgg adherence to the colonic epithelium. Previous studies suggest that Sgg adherence to colonic epithelial cells facilitates gut colonization24,25, and is linked to its ability to promote cell proliferation13 and to translocate23. Thus, adherence to the colonic epithelium is a critical early step in the pathogenic process of Sgg, however, the current mechanistic understanding of Sgg adherence is limited. Additional adherence mechanisms remain to be elucidated to fill a major knowledge gap. The hypothesis of this proposal is that two components of a type VII secretion system (T7SS) of Sgg collaboratively mediate the adherence of Sgg to the colonic epithelium by targeting a specific host cell receptor. T7SS is a specialized secretion system known to mediate pathogen interactions with the host. It has been shown to be important for the virulence and persistence of other pathogens. The Xu lab recently reported the first functional characterization of a T7SS in Sgg strain TX20005 (T7SST05) and demonstrated that this T7SS is a pathogenicity determinant of Sgg. In particular, deletion of core components of the T7SST05 secretion machinery resulted in significantly reduced capacity to adhere to colonic epithelial cells and to colonize the colon in vivo. The objectives of this proposal are to define the role of the T7SST05 components in adherence to the colonic epithelium (Aim 1) and to determine the host cell surface receptor targeted by Sgg for adherence (Aim 2). Given the limited mechanistic understanding of Sgg pathogenicity, the proposed work will provide crucial breakthroughs in identifying novel molecular players that mediate Sgg colonization of the colonic epithelium, thereby fill a major knowledge gap. Furthermore, the specific Sgg factors identified in this work are candidates for diagnostic biomarkers and clinical intervention targets, and therefore have translational potential.