{"doi":"10.1101/2022.06.09.495361","title":"Bacteriophage anti-defense genes that neutralize TIR and STING immune responses","abstract":"Summary 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.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2022,"id":298696,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":5,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9508,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":306859,"name":"Yibu Chen","orcid":"0000-0002-7889-6850","position":1,"is_corresponding":false},{"id":236690,"name":"Subarna Biswas","orcid":"0000-0003-1868-3500","position":2,"is_corresponding":false},{"id":892196,"name":"Ethan Canfield","orcid":null,"position":3,"is_corresponding":false},{"id":987700,"name":"Douglas E. Feldman","orcid":"0000-0003-0659-0788","position":4,"is_corresponding":false},{"id":988038,"name":"Pei‐Yin Ho","orcid":null,"position":0,"is_corresponding":true}],"reference_count":41,"raw_metadata":null,"created_at":"2026-07-19T00:31:36.269611Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}