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Peer-reviewedCC BYCell

Systematic discovery of pathogen effector functions across human pathogens and pathways

  • Tomás Pachano1
  • He Leng2,3
  • Guillaume Dugied2,3
  • Travis Tribble4,5
  • Vincent Loubière1
  • Yeojin Lee6,1
  • Felix Rauh1,7
  • Victor Manon8,1
  • Kevin Yuan4,9
  • Jocelyn Nurtanto10,11
  • Alexander Schleiffer1,12
  • Veronika Young9,13
13 more authors
  • Benjamin Weller9,13
  • Eleanor A Lyons14,15
  • Matthew R. Hass16,17
  • Leah Claire Kottyan18,19
  • Matthew T. Weirauch18,9
  • Juan I. Fuxman Bass15,7
  • Hayley J. Newton20,1
  • Alexander W. Ensminger21,3
  • Pascal Falter‐Braun22
  • Jue Chen23
  • Daniel Schramek10
  • Alexander Stark24
  • Mikko Taipale25
25 affiliations
  1. 1Research Institute of Molecular Pathology (IMP), Vienna Biocenter (VBC), Vienna, Austria
  2. 2Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, Ontario
  3. 3Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Ontario, Canada
  4. 4Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, Ontario; Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada
  5. 5Department of Molecular Genetics, University of Toronto, Ontario, Canada
  6. 6Centre for Molecular and Systems Biology, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada
  7. 7Centre for Molecular and Systems Biology, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada
  8. 8Howard Hughes Medical Institute, Chevy Chase, MD, USA; Weill Cornell/Rockefeller/Sloan Kettering Tri-Institutional MD-PhD Program, New York, NY, USA
  9. 9Institute of Network Biology (INET), Molecular Targets and Therapeutics Center (MTTC), Helmholtz Munich, German Research Center for Environmental Health, Neuherberg, Germany
  10. 10Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada; Centre for Molecular and Systems Biology, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada
  11. 11Department of Microbiology and Immunology, University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia
  12. 12Center for Autoimmune Genomics and Etiology, Division of Allergy & Immunology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
  13. 13Center for Autoimmune Genomics and Etiology, Division of Allergy & Immunology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA and Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA
  14. 14Department of Microbiology and Immunology, University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, Australia
  15. 15Biology Department and Bioinformatics Program, Boston University, Boston, MA, USA
  16. 16Center for Autoimmune Genomics and Etiology, Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
  17. 17Infection Program, Monash Biomedicine Discovery Institute and Department of Microbiology, Monash University, Clayton, Victoria, Australia
  18. 18Center for Autoimmune Genomics and Etiology, Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA
  19. 19Department of Biochemistry, University of Toronto, Toronto, Ontario, Canada
  20. 20Infection Program, Monash Biomedicine Discovery Institute and Department of Microbiology, Monash University, Clayton, VIC, Australia
  21. 21Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada; Department of Biochemistry, University of Toronto, Toronto, ON, Canada
  22. 22Institute of Network Biology (INET), Molecular Targets and Therapeutics Center (MTTC), Helmholtz Munich, German Research Center for Environmental Health, Neuherberg, Germany; Microbe-Host Interactions, Faculty of Biology, Ludwig-Maximilians-Universität (LMU) München, Planegg-Martinsried, Germany
  23. 23Howard Hughes Medical Institute, Chevy Chase, MD, USA; Laboratory of Membrane Biophysics and Biology, The Rockefeller University, New York, NY, USA
  24. 24Research Institute of Molecular Pathology (IMP), Vienna Biocenter (VBC), Vienna, Austria; Medical University of Vienna, Vienna Biocenter (VBC), Vienna, Austria. Electronic address: [email protected]
  25. 25Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, Ontario; Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada. Electronic address: [email protected]
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Abstract

Pathogens deploy effector proteins to exploit host cell biology, and most effector open reading frames (ORFs) are rapidly evolving and lack functional annotation. We developed the effector ORFeome (eORFeome), a scalable functional genomics platform encompassing 3,835 effector ORFs from diverse viruses, bacteria, and parasites. High-throughput barcoded screens across nuclear factor κB (NF-κB), apoptosis, p53, cGAS-STING, and major histocompatibility complex class I (MHC class I) pathways revealed novel pathway-modulating functions for hundreds of uncharacterized eORFs, unexpected activities of known effectors, and distinct pathway-specific functions encoded by single ORFs. Illustrating the power of this approach, we identified 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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Cite

BibTeXRIS
BibTeX
@article{pachano2026systematic,
  title = {{Systematic discovery of pathogen effector functions across human pathogens and pathways}},
  author = {Tomás Pachano and He Leng and Guillaume Dugied and Travis Tribble and Vincent Loubière and Yeojin Lee and Felix Rauh and Victor Manon and Kevin Yuan and Jocelyn Nurtanto and Alexander Schleiffer and Veronika Young and Benjamin Weller and Eleanor A Lyons and Matthew R. Hass and Leah Claire Kottyan and Matthew T. Weirauch and Juan I. Fuxman Bass and Hayley J. Newton and Alexander W. Ensminger and Pascal Falter‐Braun and Jue Chen and Daniel Schramek and Alexander Stark and Mikko Taipale},
  journal = {Cell},
  year = {2026},
  month = jun,
  doi = {10.1016/j.cell.2026.06.017},
  url = {https://doi.org/10.1016/j.cell.2026.06.017},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - Systematic discovery of pathogen effector functions across human pathogens and pathways
AU  - Tomás Pachano
AU  - He Leng
AU  - Guillaume Dugied
AU  - Travis Tribble
AU  - Vincent Loubière
AU  - Yeojin Lee
AU  - Felix Rauh
AU  - Victor Manon
AU  - Kevin Yuan
AU  - Jocelyn Nurtanto
AU  - Alexander Schleiffer
AU  - Veronika Young
AU  - Benjamin Weller
AU  - Eleanor A Lyons
AU  - Matthew R. Hass
AU  - Leah Claire Kottyan
AU  - Matthew T. Weirauch
AU  - Juan I. Fuxman Bass
AU  - Hayley J. Newton
AU  - Alexander W. Ensminger
AU  - Pascal Falter‐Braun
AU  - Jue Chen
AU  - Daniel Schramek
AU  - Alexander Stark
AU  - Mikko Taipale
PY  - 2026
DA  - 2026/06/30
JO  - Cell
DO  - 10.1016/j.cell.2026.06.017
UR  - https://doi.org/10.1016/j.cell.2026.06.017
AB  - Pathogens deploy effector proteins to exploit host cell biology, and most effector open reading frames (ORFs) are rapidly evolving and lack functional annotation. We developed the effector ORFeome (eORFeome), a scalable functional genomics platform encompassing 3,835 effector ORFs from diverse viruses, bacteria, and parasites. High-throughput barcoded screens across nuclear factor κB (NF-κB), apoptosis, p53, cGAS-STING, and major histocompatibility complex class I (MHC class I) pathways revealed novel pathway-modulating functions for hundreds of uncharacterized eORFs, unexpected activities of known effectors, and distinct pathway-specific functions encoded by single ORFs. Illustrating the power of this approach, we identified 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.
SN  - 0092-8674
SN  - 1097-4172
ER  -