VeSPath

Hemolytic uremic syndrome (HUS) is the most common etiology of acute renal failure in pediatrics. The classic etiology of HUS is acute colitis due to infection with enterohemorrhagic Escherichia coli (EHEC). The key virulence factor of EHEC is Shigatoxin (Stx), which is massively released into the intestinal lumen. Glomerular endothelial cells are the main targets of Stx toxin which, after binding to its specific receptor Gb3, induces a pro-inflammatory response involved in the recruitment and adhesion of platelets and leukocytes, contributing to the formation of thrombi that cause HUS. Stx can be found in a free form or in bacterial outer membrane vesicles (OMV). OMVs represent an alternative means for EHEC strains to deliver toxins and enhance their pathogenicity. Over the last decade, the emergence of EHEC serotype O80:H2 has been observed. This serotype is now the 2nd most common cause of pediatric HUS in France and infection with these EHECs progresses to HUS in 91% of cases (compared to 5% - 10% generally observed in EHEC infections). This increased virulence is linked to the acquisition of a virulence plasmid, absent in other EHEC strains. We have shown that this plasmid encodes a particular enzyme called HlyF that induces a massive production of particular OMVs that have the ability to block autophagic flux. We postulate that these particular OMVs by targeting host endothelial cells and platelets contribute to the hypervirulence of EHEC O80:H2 and lead to an aggravation of the pathophysiology and ultimately to HUS. By combining the complementary expertise of two teams from Toulouse, we will reveal the potential role of these nanoparticles in the aggravation of pathophysiology leading to HUS. This work will pave the way for potential new therapeutic approaches.