Toothpicks, logic, and next-generation sequencing: systematic investigation of bacteriophage-host interactions

Bacteriophages are abundant and diverse predators that drive community dynamics in many ecosystems and hold great potential for biotechnology and as therapeutics for bacterial infections. Previous research has largely explored phage-host interactions one-by-one, which limited our ability to observe phenotypic patterns, to uncover their genetic basis, and to unravel the underlying molecular mechanisms. However, the famous 'toothpicks and logic' were recently joined by large-scale sequencing of phage genomes and bacterial genome-wide screens that enable us to systematically investigate phage-host interactions. In this article, we highlight recent breakthroughs from the molecular basis of phage host range and receptor recognition over new insights into bacterial immunity to the serendipitous discovery of a new bacterial surface glycan. Future work will enable the understanding, prediction, and engineering of more complicated phage traits for new applications and extend the scope of these studies from simple test tube experiments to natural communities of phages and hosts.