Shigella flexneri is an enteric pathogen that causes massive inflammation and destruction of the human intestinal epithelium. Neutrophils are the first cells of the innate immune system recruited to the site of infection. These cells can attack microbes by phagocytosis, Neutrophil Extracellular Trap (NET) formation and degranulation. Here, we investigated how neutrophil degranulation affects virulence and show that exposure of Shigella to granular proteins enhances infection of epithelial cells. During this process, cationic granular proteins bind to the Shigella surface causing increased adhesion which ultimately leads to hyperinvasion. This effect is mediated by changes in the surface charge, since a lipopolysaccharide (LPS) mutant with a negative surface shows enhanced hyperinvasion compared with wild-type Shigella. We propose that Shigella evolved to use host defence molecules to enhance its virulence and subvert the innate immune system.