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Peer-reviewedCC BYCell Host & Microbe

Discovery of phage defense systems through component modularity networks

  • Daan F. van den Berg1
  • Ana Rita Costa1
  • Jelger Q. Esser1
  • Aswin Muralidharan1
  • Halewijn van den Bossche1
  • Desi Fierlier1
  • Alexey I. Fomenkov2
  • Ruoyue Wu3
  • Jiangbo Wei4
  • Peter Weigele2
  • Cui Liang5
  • Stan J. J. Brouns6
6 affiliations
  1. 1Department of Bionanoscience, Delft University of Technology, 2629 HZ Delft, Netherlands; Kavli Institute of Nanoscience, Delft University of Technology, 2629 HZ Delft, Netherlands
  2. 2Research Department, New England Biolabs, 240 County Road, Ipswich, MA 01938, USA
  3. 3Department of Chemistry, National University of Singapore, Singapore 117544, Singapore
  4. 4Department of Chemistry, National University of Singapore, Singapore 117544, Singapore; Department of Biological Sciences, Cancer Science Institute, National University of Singapore, Singapore 117544, Singapore
  5. 5Singapore-MIT Alliance for Research and Technology, Antimicrobial Resistance Interdisciplinary Research Group, Campus for Research Excellence and Technological Enterprise, Singapore, Singapore
  6. 6Department of Bionanoscience, Delft University of Technology, 2629 HZ Delft, Netherlands; Kavli Institute of Nanoscience, Delft University of Technology, 2629 HZ Delft, Netherlands. Electronic address: [email protected]
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Abstract

Phage defense systems in bacteria exhibit high degrees of modularity, with sensing, signal transmission, and effector enzymes frequently exchanged among phage defense gene clusters. In this study, we capitalize on this modularity to discover phage defense systems by searching for defense-associated modules in new gene contexts across Pseudomonas aeruginosa genomes. This approach reveals a large and interconnected network of modular components distributed across diverse gene clusters. From over 500 candidate defense systems, we select five for experimental testing and validate three: Dionysus, a TerB-encoding system that interferes with early phage infection (EPI) vesicle formation by jumbo phages; Ophion, a radical S-adenosyl-L-methionine (SAM)-containing system that blocks progression from the EPI vesicle to the nucleus stage during jumbo phage infection; and Hercules, a tightly regulated restriction-modification (RM)-like system. Collectively, we demonstrate that leveraging the modular architecture of phage defense systems is an effective approach to their discovery.

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Cite

BibTeXRIS
BibTeX
@article{berg2026discovery,
  title = {{Discovery of phage defense systems through component modularity networks}},
  author = {Daan F. van den Berg and Ana Rita Costa and Jelger Q. Esser and Aswin Muralidharan and Halewijn van den Bossche and Desi Fierlier and Alexey I. Fomenkov and Ruoyue Wu and Jiangbo Wei and Peter Weigele and Cui Liang and Stan J. J. Brouns},
  journal = {Cell Host \& Microbe},
  year = {2026},
  month = oct,
  doi = {10.1016/j.chom.2026.09.018},
  url = {https://doi.org/10.1016/j.chom.2026.09.018},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - Discovery of phage defense systems through component modularity networks
AU  - Daan F. van den Berg
AU  - Ana Rita Costa
AU  - Jelger Q. Esser
AU  - Aswin Muralidharan
AU  - Halewijn van den Bossche
AU  - Desi Fierlier
AU  - Alexey I. Fomenkov
AU  - Ruoyue Wu
AU  - Jiangbo Wei
AU  - Peter Weigele
AU  - Cui Liang
AU  - Stan J. J. Brouns
PY  - 2026
DA  - 2026/10/01
JO  - Cell Host & Microbe
DO  - 10.1016/j.chom.2026.09.018
UR  - https://doi.org/10.1016/j.chom.2026.09.018
AB  - Phage defense systems in bacteria exhibit high degrees of modularity, with sensing, signal transmission, and effector enzymes frequently exchanged among phage defense gene clusters. In this study, we capitalize on this modularity to discover phage defense systems by searching for defense-associated modules in new gene contexts across Pseudomonas aeruginosa genomes. This approach reveals a large and interconnected network of modular components distributed across diverse gene clusters. From over 500 candidate defense systems, we select five for experimental testing and validate three: Dionysus, a TerB-encoding system that interferes with early phage infection (EPI) vesicle formation by jumbo phages; Ophion, a radical S-adenosyl-L-methionine (SAM)-containing system that blocks progression from the EPI vesicle to the nucleus stage during jumbo phage infection; and Hercules, a tightly regulated restriction-modification (RM)-like system. Collectively, we demonstrate that leveraging the modular architecture of phage defense systems is an effective approach to their discovery.
SN  - 1931-3128
SN  - 1934-6069
ER  -