Unveiling the pathogen behind the vacuole

Many clinically relevant pathogens, including certain bacteria and protozoan parasites, have developed an intracellular lifestyle that enables them to nestle in customized vacuoles. Although these pathogens are protected from extracellular defences, recent findings indicate that host cells have evolved multiple strategies to unmask the pathogen disguised by the vacuole and thereby initiate innate immune responses. In this Opinion article, we propose and discuss models by which hosts can sense 'professional' vacuolar pathogens, and we highlight the ability of the host to target these stealthy bacteria and parasites.