Enhanced virulence and stress tolerance are signatures of epidemiologically successful Shigella sonnei

Shigellosis is a leading cause of diarrhoeal deaths worldwide, with Shigella sonnei increasingly implicated as a dominant agent. S. sonnei is divided into five monophyletic lineages all sharing a single O-antigen, yet most contemporary infections are caused by just a few clonal sub-lineages within globally dominant Lineage 3 that are quite distinct from the widely used Lineage 2 laboratory strain 53G. Factors underlying the success of these globally dominant lineages remain poorly understood in part due to a lack of complete genome sequences and available animal models. Here, we utilise a novel reference collection of representative Lineage 1, 2 and 3 isolates with complete genome sequences, and find that epidemiologically successful S. sonnei harbour fewer genes encoding putative immunogenic components whilst key virulence-associated regions (such as the type three secretion system and O-antigen) remain highly conserved. Using a zebrafish infection model, we discover that Lineage 3 isolates are most virulent, driven by significantly increased dissemination and a greater neutrophil response. We show that Lineage 3 isolates have increased tolerance to complement-mediated killing and acidic conditions alongside upregulated expression of group four capsule synthesis genes. Consistent with these observations, infection of primary human neutrophils revealed that Lineage 3 isolates are more tolerant of phagosomal killing. Together, our findings link the epidemiological success of S. sonnei to heightened virulence and stress tolerance and highlight zebrafish as a valuable platform to illuminate factors underlying establishment of Shigella epidemiological success.