Mechanism of evasion of cyclic oligonucleotide-based anti-phage signaling system

Project Summary Bacteriophages (Phages) are viruses that attack bacteria. Not only are phages valuable resources for novel biotechnological and molecular biology tools, but they can also be used in clinical settings for treating antibiotic-resistant infections. Bacteria carry many mechanisms to defend against phage infection and, in turn, phages have acquired counter-defense mechanisms to evade the protection. Many of these defense and counter-defense systems have counterparts in the eukaryotic innate immune systems. Therefore, understanding the arms race between the phages and their bacterial hosts is important for future development of phage therapy and other antiviral strategies. Here we will study how some phages evade the protection offered by a specific phage defense system present in many bacteria including some deadly pathogens. Specifically, we have identified a phage protein that antagonizes an antiviral system in the human pathogen Vibrio cholerae and other important pathogens. We will determine the counter-defense mechanism of this phage protein, and we will identify the role of this phage protein during phage infection. The investigation proposed here will not only inform the molecular mechanism of this arms race, but we will learn how phage-bacteria interaction shapes the evolution of a deadly pathogen. Our findings could have significant ramifications for improving human health.