The Viral Compendium is established, a database of over 350,000 proteins and domains from eukaryotic, bacterial, and archaeal viruses, to demonstrate that pathogen immune evasion is built upon conserved structural building blocks, revealing unified mechanisms and effectors of immune antagonism spanning all domains of life.
Abstract
Many components of human innate immunity are conserved in prokaryotes 1,2. While pathogens are known to evade host defenses 3, whether mechanisms of immune evasion share a similarly deep evolutionary or functional conservation across the tree of life remains largely unresolved. Here, we systematically explore this question by establishing The Viral Compendium (TVC), a database of over 350,000 proteins and 790,000 domains from eukaryotic, bacterial, and archaeal viruses. We find that protein structure alignments identify pan-viral clusters of proteins and domains, vastly increasing viral protein annotation rates compared to sequence-based methods. Domain co-association analysis revealed 1,351 combinations of domains that are conserved across archaeal, eukaryotic, and bacterial viruses, including fusion proteins that reconstitute the nuclease-ATPase core of the Mre11-Rad50 multiprotein complex involved in cellular DNA repair 4. Leveraging structural comparisons, we identify widely shared structural folds that mediate immune suppression: conserved phosphodiesterase folds encoded by both viral and bacterial pathogens that degrade nucleotide messengers, and double-stranded RNA binding domains employed across eukaryotic and prokaryotic viruses to suppress cellular sensing. Together, our results demonstrate that pathogen immune evasion is built upon conserved structural building blocks, revealing unified mechanisms and effectors of immune antagonism spanning all domains of life.
Innate immunity has been dissected in exquisite detail in Drosophila melanogaster, yet how immune systems diversify between species remains largely unknown. Here we compare responses to bacterial infection across five drosophilid species spanning 60 million years of divergence, from D. melanogaster to Scaptodrosophila lebanonensis. Seven-day survival after Gram-negative infection ranges from 19% to 99% and tracks inversely with bacterial load in a phylogenetically corrected model, indicating that clearance rather than tolerance drives these differences. RNA sequencing of all five species after sterile wounding or infection reveals strongly species-biased transcriptional responses to the same pathogen, together with numerous uncharacterized lineage-restricted genes, including predicted antimicrobial peptides. We chemically synthesized candidate peptides and confirmed their activity in vitro: Athelas (CG43920), Mtkl and the S. lebanonensis-specific Athelas-like are active against bacteria and fungi, while Daisho2, previously described as antifungal, also kills Gram-positive and Gram-negative bacteria. De novo assembly and machine-learning prediction recover further candidate peptides from intronic and intergenic regions missed by current annotation. Rewiring of conserved genes and turnover of young, often unannotated effectors therefore act together to diversify antibacterial defense within a single insect family. One-sentence summary Five drosophilids over 60 million years defend against bacteria differently using lineage-specific young effectors and rewired conserved genes.
The CD300 gene cluster encodes activating and inhibitory lipid-binding innate immune receptors that, in humans and mice, play important roles in immune response, including viral entry and autoimmunity. However, their broader evolutionary and functional diversification dynamics across vertebrates remain unresolved.
Genomic and transcriptomic analyses were employed to identify CD300 orthologs and paralogs across vertebrates. Numbers and combinations of CD300 genes were quantified and cataloged. AI-based protein folding tools were used to predict changes in protein structures. Recombinant forms of CD300 proteins were generated and subjected to an unbiased lipid-binding assay to identify and quantify ligand binding differences between orthologs and paralogs.
Our analyses reveal that CD300s are present across jawed vertebrates, with a pronounced pulse of gene duplication coinciding with the origin of placental mammals. Within mammals, the evolutionary trajectory of this cluster is remarkably labile. We observe dramatic lineage-specific expansions and contractions in groups such as chiropterans (bats) and cetaceans (whale and dolphins) that correspond to major events in the evolutionary history of these groups. Structural predictions suggest that these gene duplications are accompanied by corresponding changes in protein shape, including the extracellular domains that mediate lipid binding. Ongoing lipidomics-based ligand screening supports this prediction.
Our preliminary data show divergent lipid-binding profiles across CD300 paralogs, suggesting functional novelty. Together, these results position CD300s as a tractable model for understanding how the molecular diversification of clustered immune gene families corresponds to their ligand preferences likely reflecting their evolutionary histories.
NSF IOS 2419126; NSF IOS 2419127; NSF IOS 2419128
Veterinary and Comparative Immunology (VET)
Jeffrey A. Yoder, Erin S. Baker, Ian Birchler De Allende et al.· Journal of Immunology· 0 citations
The ubiquitin-proteasome system (UPS) constitutes a highly conserved regulatory hub governing protein turnover and signal transduction in eukaryotes, which precisely determines the fate of substrate proteins via dynamic and reversible ubiquitination. During long-term coevolution between plants and viruses, the UPS has evolved into a critical battlefield for host–virus arms races. Plants exploit the substrate recognition specificity and proteolytic activity of the UPS to selectively eliminate essential viral proteins required for infection, thereby establishing multilayered antiviral immune barriers. In contrast, viruses have evolved diverse effector proteins to antagonize or hijack this pathway to facilitate their replication and spread. Competitive exploitation of this shared regulatory machinery underlies the fundamental logic of bidirectional regulation in plant–virus interactions. This review systematically summarizes the molecular basis of UPS-mediated plant antiviral immunity, as well as convergent pathogenic strategies adopted by diverse viruses to perturb ubiquitin signaling, suppress host immune responses, and reprogram the intracellular environment. The work aims to provide theoretical insights for deciphering viral pathogenesis and breeding crops with durable virus resistance.
