The Arms Race Between Bacteria and Their Viruses: Update on Phage Countermeasures Against Bacterial Defence Systems

ABSTRACT

In this editorial, I summarize recent progress on phage‐encoded anti‐defence against bacterial anti‐phage systems (APS). Computational approaches based on structural predictions of co‐folding bacterial and phage proteins identified many new PAD sponge proteins. New anti‐CRISPR‐Cas systems were characterized that destroy cas12a mRNA, inactivate Cas12a by acetylation, engage the seed region of the crRNA, or prevent Cas3 from cleaving DNA. The phage defence protein Gad1 forms an octamer web that wraps around the complex of the Gabija APS. Tad1 and 2 are phage sponge proteins that sequester signalling nucleotides of the Thoeris APS. Tad3 to 7 interact directly with the ThsB sensor and Tad8 with the ThsA effector of the Thoeris APS. Phage sponge proteins were also described inactivating the CBASS and Pycsar APS. Still other phages use phosphodiesterases that cleave cyclic nucleotide signals to inactivate APS. Many bacterial APS effectors are NADase, destroying the essential metabolite NAD ⁺ . Phages evolved enzymes that resynthesize NAD ⁺ from its cleavage products or proteins directly inactivating the NADase. Many phages degrade the bacterial genome which creates signals activating the Metis or the Kongming APS. Phages counteracted these APS by suppressing pathways leading to the creation of particular mononucleotides degradation products detected by these APS. Several APS cleave specific tRNA, phages responded by mutating cleavage sites in tRNA (anti‐PARIS) or increasing tRNA expression to compensate for their destruction (anti‐Septu). Phages counteract toxin‐antitoxin APS by evolving their own antitoxin or by blocking the toxin protein. Researchers described cases where phages escaped detection by mutating phage proteins detected by bacterial sensors. Against the stringent response phages responded by destroying alarmones or inactivating enzymes producing these stress signals. The arms race between bacteria and phages can involve complicated layers of defence and anti‐defences and both bacteria and phages encode multiple defence systems.