Shigella sonneiO-antigen inhibits internalisation, vacuole escape and inflammasome activation

Abstract

AbstractTwoShigellaspecies,flexneriandsonnei, cause approximately 90% of bacterial dysentery worldwide. WhileS. flexneriis the dominant species in low-income countries,S. sonneicauses the majority of infections in middle and high-income countries.S. flexneriis a prototypic cytosolic bacterium; once intracellular it rapidly escapes the phagocytic vacuole and causes pyroptosis of macrophages, which is important for pathogenesis and bacterial spread. By contrast little is known about the invasion, vacuole escape and induction of pyroptosis duringS. sonneiinfection of macrophages. We demonstrate thatS. sonneicauses substantially less pyroptosis in human primary monocyte-derived macrophages and THP1 cells. This is due to reduced bacterial uptake and lower relative vacuole escape, which results in fewer cytosolicS. sonneiand hence reduced activation of caspase-1 inflammasomes. Mechanistically, the O-antigen, which inS. sonneiis contained in both the lipopolysaccharide and the capsule, was responsible for reduced uptake and the T3SS was required for vacuole escape. Our findings suggest thatS. sonneihas adapted to an extracellular lifestyle by incorporating additional O-antigen into its surface structures compared to otherShigellaspecies.