Viruses are the most abundant biological entities on Earth and play central roles in shaping microbiomes and influencing ecosystem functions. Yet, most viral genes remain uncharacterized, comprising w...

Human host-associated cellular products may act as induction agents for bacteriophages.

Phage defense systems in bacteria exhibit high degrees of modularity, with sensing, signal transmission, and effector enzymes frequently being exchanged among phage defense gene clusters. In this study, we capitalized on this modularity to discover phage defense systems by searching for defense-associated modules in new gene contexts. This approach revealed a large and interconnected network of modular components distributed across diverse gene clusters. From over 500 candidate defense systems, we selected nine for experimental testing and validated three: Dionysus, a TerB-encoding system that disrupts early phage infection vesicle formation by Jumbo phages; Ophion, a Radical SAM-containing system that prevents the formation of the Jumbo phage nucleus; and Ambrosia, a tightly regulated RM-like system. Collectively, we demonstrate that leveraging the modular architecture of phage defense systems is an effective approach to their discovery. ### Competing Interest Statement The authors have declared no competing interest. European Research Council, 101003229 Netherlands Organisation for Scientific Research, VI.C.192.027, OCENW.XS23.1.006 Koningin Wilhelmina Fonds, 15602

imageimageViro3D provides proteome-level, high confidence AI-protein structure predictions for >4,400 viruses, allowing mapping of form and function across the human and animal virosphere. Viro3D i...

Assembly graphs are a fundamental data structure used by genome and metagenome assemblers to represent sequences and their overlap information, facilitating the assembler to construct longer genomic f...

Antimicrobial resistance (AMR) is one of the greatest threats to global health. If unaddressed, it is projected to cause over 39 million cumulative deaths globally by 2050 (1). While resistance is a b...

Integration of plasmids into genomic epidemiology is challenging, because there are no clearly defined evolving-units (equivalent to species), and because plasmids appear to evolve as much by structur...

Bacterial defense systems present considerable barriers to both phage infection and plasmid transformation. These systems target mobile genetic elements, limiting the efficacy of bacteriophage-based t...

This Perspective discusses virus-encoded auxiliary metabolic genes and provides a framework for the biological interpretation of these genes.

Abstract. Protein structural phylogenetics is an interdisciplinary branch of molecular evolution that (i) uses 3D structural data to trace evolutionary his

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Bacteriophages are rich in genetic diversity, due to frequent horizontal transfer and recombination. This makes traditional microbial phylogenetic analyses, often based on the assumption of vertical i...

SUMMARYUnderstanding protein functions is crucial for interpreting microbial life; however, reliable function annotation remains a major challenge in computational biology. Despite significant advance...