Systematic Discovery of Pathogen Effector Functions across Human Pathogens and Pathways

Tomás Pachano; He Leng; Guillaume Dugied; Travis Tribble; Vincent Loubière; Yeojin Lee; Felix Rauh; Victor Manon; Kevin Yuan; Jocelyn Nurtanto; Alexander Schleiffer; Veronika Young; Benjamin Weller; Eleanor A Lyons; Matthew R. Hass; Leah Claire Kottyan; Matthew T. Weirauch; Juan I. Fuxman Bass; Hayley J. Newton; Alexander W. Ensminger; Pascal Falter‐Braun; Jue Chen; Daniel Schramek; Alexander Stark; Mikko Taipale

doi:10.1016/j.cell.2026.06.017

Systems BiologyCellJun 30, 2026

Peer-reviewed journal article

Systematic Discovery of Pathogen Effector Functions across Human Pathogens and Pathways

Tomás Pachano iD, He Leng iD, Guillaume Dugied iD, Travis Tribble, Vincent Loubière iD, Yeojin Lee, Felix Rauh, Victor Manon, Kevin Yuan, Jocelyn Nurtanto iD, Alexander Schleiffer iD, Veronika Young iD, Benjamin Weller iD, Eleanor A Lyons iD, Matthew R. Hass iD, Leah Claire Kottyan iD, Matthew T. Weirauch iD, Juan I. Fuxman Bass iD, Hayley J. Newton iD, Alexander W. Ensminger iD, Pascal Falter‐Braun iD, Jue Chen iD, Daniel Schramek iD, Alexander Stark iD, Mikko Taipale iD

Abstract

Pathogens deploy effector proteins to exploit host cell biology, and most pathogen open reading frames (ORFs) are rapidly evolving and lack functional annotation. We developed the eORFeome, a scalable functional genomics platform encompassing 3,835 effector ORFs from diverse viruses, bacteria, and parasites. High-throughput barcoded screens across NF{kappa}B, apoptosis, p53, cGAS-STING and MHC-I pathways revealed functions for hundreds of uncharacterized eORFs, unexpected new activities for known effectors, and distinct pathway-specific functions encoded by single ORFs. Illustrating the power of the approach, we identify HHV6A U14 as a p53 antagonist, HHV7 U21 as a dual-function STING antagonist and MHC-I antigen display inhibitor, and adenoviral 13.6K/i-leader protein as a de novo evolved TAP inhibitor that suppresses MHC-I display. These results establish a general framework for systematic effector annotation, uncover new mechanisms of host-pathogen interaction across kingdoms, and highlight pathogen effectors as a versatile toolkit for rewiring and probing human cellular pathways.

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