Discovery of twitching motility in Streptococcus gallolyticus subspecies gallolyticus and its contribution to colon cancer cell invasion

Colorectal cancer is the second most prevalent cause of cancer-related death worldwide, and Streptococcus gallolyticus subspecies gallolyticus is an emerging pathogen in humans that is strongly associated with CRC and is proposed to further exacerbate the patient’s health upon colonisation of these tumours. Sgg is the main causative agent of bacteraemia and infective endocarditis in the elderly and immunocompromised. Though Sgg is a commensal coloniser of the GIT, this opportunistic pathogen unveils its pathogenic potential upon CRC tumour colonisation. Consequently, Sgg can translocate into the host’s bloodstream where invasive infection is established. How this opportunistic pathogen accomplishes such translocation remains elusive, and answering this question is the main objective of this thesis. Though Sgg are widely accepted as a non-motile organism, this study shows for the first time that this species exhibits twitching motility. This discovery prompted an in-depth analysis of how Sgg might employ this novel phenotype in the establishment of CRC infection. The impact of metabolites associated with CRC progression on Sgg twitching motility was assessed. It was found that motility can be shut-off in the presence of specific metabolites, but it can also be enhanced in nutrient limited conditions. Twitching motility is characteristic of bacterial species that express Type IV pili, thus, whole-genome sequencing of an Sgg clinical isolate was carried out which revealed the presence of a Type IV pilus operon.
This work shows that Sgg are capable of invading CRC cells and that invasion can be significantly reduced in motility inhibiting conditions. Transmission electron microscopy shows the presence of Type IV pili-like structures present on the surface of Sgg. There is currently no treatment to combat Sgg infection of CRC tumours. This study delves into the potential use of phosphodiesterase inhibitors for preventative or interventional therapy for patients presenting with CRC, as these compounds significantly reduce the ability of Sgg to invade CRC cells. It has still not yet been confirmed how Sgg gains access to the bloodstream. This study provides evidence that Sgg is motile upon encountering CRC tumours, and that this motility drives invasion of cancer cells and potentially translocation into the blood. Twitching motility is a novel phenomenon for Sgg, and identification of this previously undiscovered pathogenic phenotype may provide a new route of research and act as a potential new target for therapeutic or vaccine design.