Poxvirus attack of anti-viral defense pathways unleashes an effector-triggered NF-?B response [RNAseq_MYXV_screen]
Effector-triggered immunity (ETI) is a form of pathogen sensing that involves detection of pathogen-encoded virulence factors or “effectors”. To discover novel ETI pathways in mammals, we developed a screening approach in which individual virulence factors are expressed in human monocytes and transcriptional responses are assessed by RNA-seq. Using this approach, we identify a poxvirus effector, myxoma virus M3.1, which elicits an anti-viral NF-?B response. We find that NF-?B is unleashed by an ETI pathway that senses M3.1 attack of two anti-viral complexes: ZAP and TBK1. NF-?? activation occurs because the proteins inhibited by M3.1—N4BP1, ZC3H12A, and TBK1—are negative regulators of NF-?B. Our results illustrate how negative regulators can function as pathogen sensors and establish a systematic approach for the discovery of ETI pathways. Overall design: Bulk RNA barcoding and sequencing of BLaER1 monocytes expressing myxoma virus open reading frames (ORFs).