Bacteriophage antidefense genes that neutralize TIR and STING immune responses

• Published in: Cell reports (Cambridge) 2023-04, Vol.42 (4), p.112305-112305, Article 112305
• Main Authors: Ho, Peiyin, Chen, Yibu, Biswas, Subarna, Canfield, Ethan, Abdolvahabi, Alireza, Feldman, Douglas E.
• Format: Article
• Language: English
• Subjects: CP: Immunology; CP: Microbiology
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2023.112305

Programmed cell suicide of infected bacteria, known as abortive infection (Abi), serves as an immune defense strategy to prevent the propagation of bacteriophage viruses. Many Abi systems utilize bespoke cyclic nucleotide immune messengers generated upon infection to mobilize cognate death effectors. Here, we identify a family of bacteriophage nucleotidyltransferases (NTases) that synthesize competitor cyclic dinucleotide (CDN) ligands and inhibit TIR NADase effectors activated via a linked STING CDN sensor domain (TIR-STING). Through a functional screen of NTase-adjacent phage genes, we uncover candidate inhibitors of cell suicide induced by heterologous expression of tonically active TIR-STING. Among these, we demonstrate that a virus MazG-like nucleotide pyrophosphohydrolase, Atd1, depletes the starvation alarmone (p)ppGpp, revealing a potential role for the alarmone-activated host toxin MazF as an executioner of TIR-driven Abi. Phage NTases and counterdefenses like Atd1 preserve host viability to ensure virus propagation and represent tools to modulate TIR and STING immune responses. [Display omitted] •Bacteriophage viruses encode compact NTases that synthesize cyclic dinucleotides•Phage-generated cyclic dinucleotides may competitively inhibit host STING immune sensors•A functional screen identifies Atd1, a phage MazG-like suppressor of TIR-STING cell suicide•Atd1 depletes the (p)ppGpp alarmone, implicating host toxin MazF in TIR-directed cell death Ho et al. identify a family of bacteriophage nucleotidyltransferases (NTases) that synthesize cyclic dinucleotides and inhibit immune effectors containing a STING sensor domain. Functional screening of NTase-adjacent phage genes identifies Atd1, a MazG-like enzyme that depletes the (p)ppGpp starvation alarmone, blocking activation of the MazF toxin by TIR death effectors.