Following contact with the epithelium, the enteric intracellular bacterial pathogen Shigella flexneri invades epithelial cells and escapes intracellular phagosomal destruction using its type III secretion system (T3SS). The bacterium replicates within the host cell cytosol and spreads between cells using actin-based motility, which is mediated by the virulence factor IcsA (VirG). Whereas S. flexneri invasion is well characterized, adhesion mechanisms of the bacterium remain elusive. We found that IcsA also functions as an adhesin that is both necessary and sufficient to promote contact with host cells. As adhesion can be beneficial or deleterious depending on the host cell type, S. flexneri regulates IcsA-dependent adhesion. Activation of the T3SS in response to the bile salt deoxycholate triggers IcsA-dependent adhesion and enhances pathogen invasion. IcsA-dependent adhesion contributes to virulence in a mouse model of shigellosis, underscoring the importance of this adhesin to S. flexneri pathogenesis. ; Anna Brotcke Zumsteg, Christian Goosmann, Volker Brinkmann, Renato Morona, Arturo Zychlinsky