The Enemy of My Enemy: New Insights Regarding Bacteriophage–Mammalian Cell Interactions

Bacteriophages (phages) are the most abundant biological entity in the human body, but until recently the role that phages play in human health was not well characterized. Although phages do not cause infections in human cells, phages can alter the severity of bacterial infections by the dissemination of virulence factors amongst bacterial hosts. Recent studies, made possible with advances in genome engineering and microscopy, have uncovered a novel role for phages in the human body – the ability to modulate the physiology of the mammalian cells that can harbor intracellular bacteria. In this review, we synthesize key results on how phages traverse through mammalian cells – including uptake, distribution, and interaction with intracellular receptors – highlighting how these steps in turn influence host cell killing of bacteria. We discuss the implications of the growing field of phage–mammalian cell interactions for phage therapy. Phages can enter mammalian cells through similar pathways to mammalian viruses.With high-resolution microscopy and fluorescent reporters, phages have been found inside endosomes, lysosomes, Golgi, cytoplasm, and the nucleus of mammalian cells.Inside endosomal compartments, phages can activate Toll-like receptors, stimulate cytokine expression, and alter immune cell polarization.In both the phagosome and the cytosol, phages can interact with and kill host bacteria.Phage DNA can reach the nucleus of mammalian cells and express native genes.