Research Interests
1. How do bacteria thwart phage infection?
Dozens of new bacterial anti-phage systems have recently been found. Many of these systems are homologs of key eukaryotic immune proteins, such as cGAS and gasdermins, which appear to have originated in prokaryotes. While some anti-phage defense systems target phage directly (e.g. Cas12), others trigger cell death or dormancy to abort the infection and prevent phage spread (e.g. CBASS). We are interested in exploring the molecular mechanisms these systems use to detect and thwart phage infection.
2. How do phages overcome multi-layered bacterial defense systems?
Many bacteria encode multiple anti-phage systems, and closely related strains can differ dramatically in their defense repertoire. However, it is unclear how phages overcome these multi-layered defenses to replicate and spread throughout the population. Although a few phage-encoded inhibitors and evasion strategies have been uncovered, it remains a mystery how phages overcome most defense systems. We will explore the dark matter of phage genomes to discover and characterize these evasion mechanisms.
3. How does a phage-encoded anti-CRISPR trigger translation-dependent destruction of Cas12a mRNA?
We discovered a phage-encoded anti-CRISPR (AcrVA2) that inhibits Cas12a by binding to its N-terminal polypeptide and triggering destruction of its mRNA. AcrVA2 binds conserved and functionally important amino acids in Cas12a, allowing it to downregulate divergent Cas12a sequences while constraining escape. This novel mechanism of molecular antagonism appears to be widespread against other genes in bacteria. In the future, we will explore this mechanism of polypeptide recognition and mRNA destruction while identifying other targets. We will also apply this mechanism to regulate expression of other genes in bacteria and beyond.