For more than 20 years, my research interest has focused on host-pathogen interactions.
In the last decade, I have focused on the role of cell-wall anchored proteins in Streptococcus agalactiae (or GBS). Our group is leader in the study of pilus biogenesis, role in the infectious process, and regulation of their expression in gram-positive bacteria.
Over the past 4 years, we have extended our work on GBS pili to the related human pathogen Streptococcus gallolyticus, an emerging cause of septicemia and infective endocarditis in the elderly, that has been epidemiologically linked to colonic malignancies.
Our main goal is to determine whether the association of S. gallolyticus with colon cancer is causal or incidental.
The first complete genome of S. gallolyticus, strain UCN34, was published by our collaborators, revealing the existence of 3 pilus operons (pil1, pil2 and pil3). Among these, pil1 and pil3 are the most conserved loci.
We have developed the first genetic tools to inactivate or overexpress specific genes in S. gallolyticus (Danne et al., 2013) and were able to show that the pilus Pil1 is a virulence factor that allows S. gallolyticus to bind to collagen and to promote endocarditis in a rat experimental model (Danne et al., 2011).
Pili are highly immunogenic proteins proposed as vaccine candidates in pathogenic streptococci whose expression bears a fitness cost due to the selective pressure of host immune responses. We have characterized, at the molecular level, a novel regulatory mechanism responsible for Pil1 and Pil3 heterogeneous expression combining phase variation in the leader peptide and transcriptional attenuation. This simple and robust mechanism controls a stochastic heterogeneous pilus expression, which is important for evading the host immune system while ensuring optimal tissue colonization (Danne et al., 2014).
We also studied the Pil3 pilus that encodes a putative mucus-binding protein. We demonstrated that Pil3 is required for binding to colonic mucins and for the colonization of mice distal colon (Martins et al., 2015; Martins et al., 2016).
We recently showed that Sgg is able to produce a specific bacteriocin, named gallocin, which contributes to enhance bacterial colon colonization in tumor bearing mice (Aymeric et al., 2018). Gallocin is a two-component bacteriocin which was shown to inhibit the growth of closely related Enterococci commensals, thus creating an appropriate colonization niche for Sgg. Gallocin activity is strongly potentiated in the presence of secondary bile acids such as deoxycholic and lithocholic acids, which are known risk factors for CRC. Indeed, following a one shot inoculation, Sgg UCN34 persisted for 3 months in adenoma-bearing host, whereas it was progressively excluded from the gut of healthy mice. This colonization advantage was lost with the gallocin-deficient mutant. We further unraveled a new link between Wnt pathway activation, an early step in CRC development, and increased luminal concentration of secondary bile acids by showing that Wnt activation resulted in decreased expression of the apical bile acids transporter Slc10A2 and reduced luminal bile acids reabsorption. Apc mutation, increased carcinogenic secondary bile acids and SGG colonization may thus be part of a vicious pro-tumoral triangle.
Increasing our molecular knowledge about the specific traits of S. gallolyticus that contribute to CRC initiation and progression should help in the development of new strategies for CRC diagnosis, treatment and prevention (for recent reviews, Pasquereau-Kotula et al., 2018; Aymeric et al., 2018).