All in—Multiple parallel strategies for intracellular delivery by bacterial pathogens

Microbial pathogens have developed intriguing molecular strategies to modulate and/or control host cell functions to ensure their own survival and replication. During this molecular interplay between microbes and their respective hosts especially secreted virulence factors play a major role. These factors not only include a plethora of cytotoxins but also sophisticated effector proteins targeting intracellular decision points leading to inhibition of defense responses - and/or even to cell death. To be effective, most of these secreted factors have to get across the cytoplasmic membrane and reach their targets in the cytoplasm. Apparently, pathogens use multiple mechanisms to deliver virulence factors to their cytoplasmic destination. Here, we exemplarily discuss the recently emerging scenario of parallel strategies for the intracellular deployment of toxins and effector proteins of Gram-negative pathogens with a special focus on pathogenic Escherichia coli. These pathogens employ various nanomachines such as the type III secretion system (T3SS), cell-penetrating effector proteins (CPE), and the wrapping of virulence factors in outer membrane vesicles (OMV) for protection and parallel delivery. As intracellular delivery remains a major problem in drug development, potential therapeutic applications based on these bacterial strategies will be briefly discussed.