Researchers have developed a screening method to identify effector-triggered immunity (ETI) in human cells using the expression of individual myxoma virus (MYXV) virulence factors in BLaER1 human monocytic cells and subsequent RNA sequencing.[1][2][3] This screen revealed a previously undescribed MYXV effector M3.1 that activates NF-κB signaling in human monocytes.[1][3] The NF-κB response limits MYXV replication and arises as a host ETI response to M3.1 attack on antiviral pathways.[1] M3.1 deactivates the ZAP complex, TRIM25, and TBK1-mediated type I interferon signaling.[1][3] NF-κB activation occurs indirectly, because proteins inhibited by M3.1 (N4BP1, ZC3H12A and TBK1) are also negative regulators of NF-κB.[1] The attack of the viral effector on these dual-functioning antiviral proteins thus releases a compensatory NF-κB response.[1][3] This study introduces a new model where negative immune regulators serve as pathogen sensors in host-pathogen competition.[1]