Poster Presentation 14th Lorne Infection and Immunity 2024

Helicobacter pylori cytotoxin, VacA, modulates conventional dendritic cell maturation and hijacks extracellular vesicles to dysregulate immune cell functions (#139)

Ruby Gorman-Batt 1 , Meredith O'Keeffe 1 , Terry Kwok-Schuelein 1
  1. Biomedical Discovery Institute, Monash University, Clayton, VICTORIA, Australia

Helicobacter pylori (Hp) is a carcinogenic bacterium that persistently infects ~50 % of the world’s population and is the greatest risk factor for the development of gastric cancer (GC). Accumulating evidence suggests that a key Hp virulence factor, the Vacuolating cytotoxin A (VacA), facilitates Hp persistence by limiting immune cell functions. Of interest, VacA has been shown to alter the maturation status of dendritic cells (DCs), professional phagocytic cells that are critical for the induction of protective immunity. These cells are key for bacterial and tumour antigen presentation, meaning they likely participate in the progression of Hp-induced gastric cancer. However, studies to date have concentrated on in vitro generated monocyte-derived DC that likely do not represent in vivo cells. Thus, we aimed to characterise the interactions between VacA and the conventional type 1 cDCs (cDC1s). Here, we show that VacA interferes with cDC1 maturation and activation. In addition, we found that VacA interacts with the cell membrane without being phagocytosed by the cDC1s. Instead, the toxin localised to extracellular vesicles (EVs) being shed from the cDC1 surface. Moreover, VacA+-EVs were enriched in key markers of immune cell functions and possessed the ability to deliver VacA to naïve immune cells. This study reveals that VacA specifically binds EV at the cDC1 surface, altering cDC1 and DC-EV immune marker composition. We propose that VacA perturbs cDC1 maturation and hijacks DC-EVs to dysregulate immune cell signalling, assisting in the chronic persistence of Hp. Our findings highlight a previously unrecognised role of host EVs in bacterial pathogenesis.