TY - JOUR T1 - Bacteriophage anti-defense genes that neutralize TIR and STING immune responses JF - bioRxiv DO - 10.1101/2022.06.09.495361 SP - 2022.06.09.495361 AU - Peiyin Ho AU - Yibu Chen AU - Subarna Biswas AU - Ethan Canfield AU - Douglas E. Feldman Y1 - 2022/01/01 UR - http://biorxiv.org/content/early/2022/06/30/2022.06.09.495361.abstract N2 - Programmed cell suicide of infected bacteria, known as abortive infection (Abi), serves as a central immune defense strategy to prevent the spread of bacteriophage viruses and other invasive genetic elements across a population. Many Abi systems utilize bespoke cyclic nucleotide immune messengers generated upon infection to rapidly mobilize cognate death effectors. Here, we identify a large family of bacteriophage nucleotidyltransferases (NTases) that synthesize competitor cyclic dinucleotide (CDN) ligands, inhibiting NAD-depleting TIR effectors activated by a linked STING CDN sensor domain. Virus NTase genes are positioned within genomic regions containing other anti-defense genes, and through a functional screen, we uncover candidate anti-TIR defense (Atd) genes that confer protection against TIR-STING cytotoxicity. We show that a virus MazG-like nucleotide pyrophosphatase identified in the screen, Atd1, depletes the starvation alarmone (p)ppGpp, revealing a role for the alarmone-activated host toxin MazF as a key executioner of TIR-directed abortive infection. Phage NTases and counter-defenses like Atd1 preserve host viability to ensure virus propagation, and may be exploited as tools to modulate TIR and STING immune responses.Competing Interest StatementThe authors have declared no competing interest. ER -