The dynamic interplay of bacteriophage, bacteria and the mammalian host during phage therapy

For decades, biomedically centered studies of bacteria have focused on mechanistic drivers of disease in their mammalian hosts. Likewise, molecular studies of bacteriophage have centered on understanding mechanisms by which bacteriophage exploit the intracellular environment of their bacterial hosts. These binary interactions – bacteriophage infect bacteria and bacteria infect eukaryotic hosts – have remained largely separate lines of inquiry. However, recent evidence demonstrates how tripartite interactions between bacteriophage, bacteria and the eukaryotic host shape the dynamics and fate of each component. In this perspective, we provide an overview of different ways in which bacteriophage ecology modulates bacterial infections along a spectrum of positive to negative impacts on a mammalian host. We also examine how coevolutionary processes over longer timescales may change the valence of these interactions. We argue that anticipating both ecological and evolutionary dynamics is key to understand and control tripartite interactions and ultimately to the success or failure of phage therapy.