Anti-phage defense as a driver of molecular innovation

Abstract

Bacteriophages, or phages for short, pose a near-constant threat to the bacteria they infect. Billions of years of conflict has been a catalyzing force for the creation of bacterial defense systems and corresponding phage evasion strategies. To counter phage predation, bacteria have developed a vast diversity of enzyme chemistries and molecular sensing mechanisms whose study has produced new biotechnological tools and insights into our own immune systems. In this work, I have investigated anti-phage defense mechanisms at multiple scales using a combination of genetic, biochemical, and bioinformatic approaches. First, I characterized the mechanism of action of the anti-phage defense system CmdTAC, a toxin-antitoxin-chaperone system that recognizes a viral structural protein to activate a novel mRNA ADP-ribosyltransferase, thereby halting infection. Next, I examined the diversity and distribution of anti-phage mechanisms encoded by E. coli lysogenic phages – phages capable of integrating into and lying dormant within their bacterial hosts. This analysis uncovered overlooked classes of lysogenic phages harboring novel candidate defense systems, including one newly validated system with no detectable homology to previously known mechanisms. Together, this work broadens our understanding of bacterial immune systems, expands the pool of known enzyme chemistries, and highlights areas where continued study can reveal additional mechanisms of anti-phage defense.