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Systematic Discovery of Pathogen Effector Functions across Human Pathogens and Pathways.

Tomas Pachano1, He Leng2, Guillaume Dugied2

  • 1Research Institute of Molecular Pathology (IMP), Vienna Biocenter (VBC), Vienna, Austria.

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|December 3, 2025
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Summary
This summary is machine-generated.

Scientists created a large platform to study pathogen effector proteins, revealing new functions for hundreds of uncharacterized proteins and uncovering novel host-pathogen interactions. This work provides a new framework for understanding how pathogens manipulate host cells.

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Area of Science:

  • Microbiology
  • Genomics
  • Immunology

Background:

  • Pathogens utilize effector proteins to manipulate host cell functions.
  • Most pathogen effector open reading frames (ORFs) are uncharacterized due to rapid evolution.
  • Understanding effector functions is crucial for deciphering host-pathogen interactions.

Purpose of the Study:

  • To develop a scalable functional genomics platform for annotating pathogen effector ORFs.
  • To systematically investigate the functions of a large collection of effector proteins across key host pathways.
  • To uncover novel mechanisms of host cell manipulation by pathogens.

Main Methods:

  • Development of the eORFeome platform, comprising 3,835 effector ORFs from diverse pathogens.
  • High-throughput barcoded screens across the NFκB, apoptosis, p53, cGAS-STING, and MHC-I pathways.
  • Functional characterization of uncharacterized and known effector proteins.

Main Results:

  • Hundreds of uncharacterized effector ORFs were assigned functions.
  • New activities were discovered for known effector proteins.
  • Specific examples include HHV6A U14 as a p53 antagonist, HHV7 U21 as a STING antagonist and MHC-I inhibitor, and an adenovirus protein as a TAP inhibitor.

Conclusions:

  • The eORFeome platform provides a general framework for systematic effector annotation.
  • New mechanisms of host-pathogen interaction across different kingdoms were uncovered.
  • Pathogen effectors serve as versatile tools for studying and manipulating human cellular pathways.