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Exploring the diversity of anti-defense systems across prokaryotes, phages, and mobile genetic elements
Open accessPreprint — published as 10.1093/nar/gkae1171
Abstract
The co-evolution of prokaryotes, phages, and mobile genetic elements (MGEs) over the past billions of years has driven the emergence and diversification of defense and anti-defense systems alike. Anti-defense proteins have diverse functional domains, sequences, and are typically small, creating a challenge to detect anti-defense homologs across the prokaryotic genomes. To date, no tools comprehensively annotate anti-defense proteins within a desired genome or MGE. Here, we developed "AntiDefenseFinder" - a free open-source tool and web service that detects 156 anti-defense systems (of one or more proteins) in any genomic sequence. Using this dataset, we identified 47,981 anti-defense systems distributed across prokaryotes, phage, and MGEs. We found that some genes co-localize in "anti-defense islands", including E. coli T4 and Lambda phages, although many are standalone. Out of the 112 systems detected in bacteria, 100 systems localize only or preferentially in prophages, plasmids, phage satellites, integrons, and integrative and conjugative elements. However, over 80% of anti-Pycsar protein 1 (Apyc1) resides in non-mobile regions of bacteria. Evolutionary and functional analyses revealed that Apyc1 likely originated in bacteria to regulate cNMP signaling, but was co-opted multiple times by phages to overcome cNMP-utilizing defenses. With the AntiDefenseFinder tool, we hope to facilitate the identification of the full repertoire of anti-defense systems in MGEs, the discovery of new protein functions, and a deeper understanding of host-pathogen arms race.
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“Although it is established that plasmids carry anti-defence genes [ 9 ], far less is known about their strategies for evasion.”
InfluentialGenomic islands in Pseudomonas encode modular hotspots of defence and anti-defence systems
Garrett, S. R., Tucker, S. K., Pavelka, V., Roe, A., & Mariano, G. (2025) · NAR Genomics and Bioinformatics · doi:10.1093/nargab/lqaf148 · Cited by 4
“Given that MGEs must overcome host defences to establish themselves within bacterial populations, it is unsurprising that anti-defence proteins are frequently encoded not only by lytic phages but also by MGEs [ 2 , 26 , 27 ].”
Influentialvan Beljouw, S. P. B., & Li, Y. (2026) · Nature Communications · doi:10.1038/s41467-026-74333-0 · Cited by 3
“The ongoing arms race between MGEs and their bacterial hosts has resulted in the emergence of diverse defense and counter-defense strategies 138,139 .”
AcrDB update: Predicted 3D structures of anti‐ CRISPRs in human gut viromes
Khatri, M., Shanmugam, N. R. S., Zhang, X., Patel, R. S. K. R., & Yin, Y. (2025) · Protein Science · doi:10.1002/pro.70177 · Cited by 3
Lan, M.-M., Xu, L., Han, Y., Cui, T., Qiao, Z., Teng, Y.-B., Wang, N., & Bao, H.-Y. (2026) · Nucleic Acids Research · doi:10.1093/nar/gkaf1492 · Cited by 2
“The predominant chromosomal localization of NARP1 and apyc1, not confined to mobile genetic elements, has been interpreted as evidence that such genes have been stably integrated and domesticated for host-centered functions rather than acting solely as phage-encoded anti-defense factors [ 58 ].”
InfluentialFraga-Pampín, S., Osorio, C., & Vences, A. (2025) · The ISME Journal · doi:10.1093/ismejo/wraf274 · Cited by 2
“Defense and anti-defense systems were identified using DefenseFinder, AntiDe-fenseFinder tools [14, 15], and PADLOC [31].”
An expanded realm of anti-CRISPR-associated proteins and regulatory mechanisms
Feussner, M., Birkholz, N., Lee, S.-Y.-O., Beisel, C., Park, H. H., Brown, C., Fineran, P., & Weinberg, Z. (2026) · bioRxiv · doi:10.1093/nar/gkag862 · Cited by 1
“Anti-defence functions were inferred using HMMs downloaded from the Anti-Prokaryotic Immune System Database ( https://bcb.unl.edu/dbAPIS/index.php ) [ 36 ] and AntiDefenseFinder [ 37 ].”
Balancing of immune activation and suppression during phage infectionPreprint
Fedorova, I., Yue, Y., Gao, Z.-R., Grunberg, M., Wang, H., Li, J.-J., Zang, Z., Nault, D. L. D., Yang, X., Gerdt, J. P., et al. (2026) · bioRxiv · doi:10.64898/2026.06.04.730250 · Cited by 1
Self-citationA Unique Type V CRISPR-Cas System Encoded by a Group of Thermus VirusesPreprint
Trofimova, A. B., Demkina, A., Shmakov, S., Livenskyi, A., Serebryakova, M., Dmitriev, A. А., Rubinshteyn, I. D., Severinov, K., & Kolesnik, M. V. (2026) · bioRxiv · doi:10.64898/2026.04.20.719267 · Cited by 1
“Phage genomes encode various defense and counterdefense systems (5, 81).”
In silico approaches for discovering microbial antiviral defense systems
Jiang, L., Li, Y., Xie, B., Wang, L.-R., & Chen, S. (2025) · Briefings in Bioinformatics · doi:10.1093/bib/bbaf619 · Cited by 1
Single-cell-resolved natural giant virus infections reveal conserved protist immunity
Fromm, A., Alarcón-Schumacher, T., Bellas, C., Shaler, T. S., Schatz, D., Schön, M., Schewe, N., Kopejtka, K., Sommaruga, R., Aylward, F., et al. (2026) · bioRxiv · doi:10.64898/2026.10.11.758280
“Co-option of host defense mechanisms by viruses has previously been described in bacteriophages; for example, the anti-Pycsar protein Apyc1 counteracts bacterial cyclic nucleotide signaling defenses ( 30 ).”
Community-level diversity of viral counter-defensomesPreprint
Beavogui, A., Silva, L. H. D. S. E., Gomes, I. D. G. M., Doladille, L., Wiart, N., Wincker, P., & Oliveira, P. H. (2026) · bioRxiv · doi:10.64898/2026.08.10.744029
“Phages, in turn, have responded by evolving a growing array of counter-defense strategies capable of targeting bacterial defensomes at multiple levels, with more than 150 systems and 27 families described to date 20 .”
InfluentialHuang, D., Yang, Y.-Y., Wu, R., Balcázar, J., Alvarez, P. J. J., Zhou, J., & Yu, P.-F. (2026) · bioRxiv · doi:10.64898/2026.09.28.755093
“Notably, prokaryotic genomes often encode multiple antiviral defense systems, and their compositions vary substantially across microbial lineages[37, 68].”
InfluentialAcquisition and erosion of toxin–antitoxin systems in bacterial chromosomes
Belot, L., Payelleville, A., Jurėnas, D., Rocha, E. P. C., & van Melderen, L. (2026) · Molecular biology and evolution · doi:10.1093/molbev/msag230
Selective elimination of donor bacteria to analyze plasmid reactions during conjugative transfer
Wen, M., Mettouchi, E., Sánchez, A. L., & Yamaichi, Y. (2026) · Biology Methods and Protocols · doi:10.1093/biomethods/bpag038
Rahimian, M., & Aghazadeh-Soltan-Ahmadi, M. (2026) · BMC Microbiology · doi:10.1186/s12866-026-05295-y
“For example, Bernheim et al. report that some anti-defense genes co-localize in islands in phages (e.g. E. coli T4 and lambda), although many anti-defense genes are found alone [53].”
InfluentialEco-evolutionary dynamics of defense systems in mobile genetic elements: Cui bono?
Iranzo, J., Wolf, Y., & Koonin, E. (2026) · bioRxiv · doi:10.64898/2026.05.25.727639
“In the course of the host-parasite arms race, MGEs have evolved a commensurate diversity of counter-defense mechanisms, many of which remain to be characterized [9-11].”
Rodera-Fernandez, P., Sastre-Domínguez, J., Costas, C., de la Fuente, J., Valle, A. A.-D., Hernández-García, M., Cantón, R., Santos-Lopez, A., & Millán, Á. S. (2026) · bioRxiv · doi:10.64898/2026.05.18.725816
“The most widespread bacterial antidefense system is anti-RM, which prevents the formation of restriction barriers that block foreign DNA influx [61, 62].”
Eremina, A., Iarema, P., Kotovskaya, O., Shenfeld, A. A., Demkina, A., Ivanova, K., Drobiazko, A., Morozova, D., Severinov, K., & Isaev, A. B. (2026) · International Journal of Molecular Sciences · doi:10.3390/ijms27093756
“DefenseFinder v. 2.0.1 was implemented to search for antidefense systems [52,53].”
InfluentialCalin, R., Vilaplana, B. B., Gedeon, J., Capton, E., François, A., Galinat, C., Saffarian, A., Pierrat, G., Benzerara, Y., Wurtzer, S., et al. (2026) · bioRxiv · doi:10.64898/2026.03.23.713486
Docherty, J. A. D., Kuzub, N., Fernández-Pato, A., Sinha, T., George, S., Andreu-Sánchez, S., Kavanal, Y., Gois, M. F. B., Ennis, D., Mallon, C., et al. (2026) · bioRxiv · doi:10.64898/2026.02.18.706556
Li, R., Wan, F., Wei, J.-X., Wen, Y., Jia, P., Lin, P., Liu, L., & Wu, M. (2026) · Sichuan da xue xue bao. Yi xue ban = Journal of Sichuan University. Medical science edition · doi:10.12182/20260160205
Bours-Lugo, D. P., Hurtado-Ramírez, J., Hernández-Mendoza, A., González, R. A., Ochoa-Leyva, A., & López-Leal, G. (2026) · Microbiology · doi:10.1099/mic.0.001660
“Bacteria can encode diverse antiviral defence systems against phage infection, while phages develop strategies to evade these systems [15].”
InfluentialBoreal and subarctic freshwaters harbour a diversity of jumbophages
Niemi, M., Karneyeva, K., Sundberg, L.-R., Oksanen, H. M., & Laanto, E. (2026) · bioRxiv · doi:10.1093/ismeco/ycag239
“Additionally, Ahti encoded a putative NAD + reconstitution pathway 1 (NARP1), listed under the NADP category in AntiDefenseFinder, which represents a predicted phage anti-defence strategy against NAD + - depleting bacterial defence systems [ 19, 59] ( Table S9).”
Host breed and geography shape the antiviral defense landscape of the bovine rumen microbiome
Faleiros, C. A., Gonçalves, O. S., Nunes, A. T., Pires, C. S., Poleti, M., & Fukumasu, H. (2026) · ISME Communications · doi:10.1093/ismeco/ycag162
“In response to DS, viruses have also developed immune strategies such as anti-CRISPR proteins and many others, which make up anti-defense mechanisms [ 25, 26].”
Su, L., Mara, P., Edgcomb, V., & Teske, A. P. (2026) · ISME Communications · doi:10.1093/ismeco/ycag200
“Collectively, the pan-immune system that includes these mechanisms has been termed the prokaryotic ‘immune system’ [ 4], which also includes additional newly discovered mechanisms that remain poorly understood [ 3].”
Unraveling the diversity, function, and virus–host interactions of archaeal proviruses
Zhao, Y., Liu, P., Chen, L., Feng, M., Wen, R., Zhang, Z., Zhang, X., & Chi, H. (2026) · ISME Communications · doi:10.1093/ismeco/ycag243
“Meanwhile, persistent viral pressure has driven the evolution of sophisticated host defense systems, such as restriction–modification (RM) systems and CRISPR –Cas [ 34], which in turn has led to the emergence of diverse viral anti-defense mechanisms [ 35].”
Synteny and linkage decay in bacteriophage pangenomesPreprint
Fendley, J. M., Molari, M., Neher, R., & Shraiman, B. I. (2025) · bioRxiv · doi:10.1101/2025.08.12.669904
“Inspired by defense-islands in bacteria [27], we were particularly interested in looking for defense and anti-defense genes, so in addition to the database annotations, we used DefenseFinder [32, 33] to locate defense and anti-defense genes.”
A bacterial CARD-NLR immune system controls the release of gene transfer agents
Banks, E. J., Bárdy, P., Tran, N., Nguyen, P. M., Maqbool, A., & Le, T. B. K. (2025) · bioRxiv · doi:10.1101/2025.05.08.652646
Matthews, A. C., & Dimitriu, T. (2025) · bioRxiv · doi:10.1101/2025.03.30.646151
“Plasmids have evolved multiple anti-defence mechanisms (Tesson et al., 2024) as well as defence avoidance strategies (Shaw et al., 2023).”
Metadata
- Authors
- Tesson, F., Huiting, E., Wei, L., Ren, J., Johnson, M. C., Planel, R., Cury, J., Feng, Y., Bondy-Denomy, J., & Bernheim, A.
- Affiliations
- Centre National de la Recherche Scientifique (FR)
- University of California, San Francisco (US)
- State Key Laboratory of Chemical Resource Engineering (CN)
- Institute of Plant Protection (CN)
- Corresponding author
- Bernheim, Aude
- ORCID
- Venue
- Nucleic Acids Research
- Publisher
- openRxiv
- Published
- 2024-08-21
- Volume
- 53
- Issue
- 1
- ISSN
- 0305-1048 (ISSN-L)
- PMC
- PMC11724313
- OpenAlex
- W4405220483
- Cited by
- 75
- References
- 62
- Citations by year
- 2026: 37 · 2025: 34 · 2024: 4
- FWCI
- 20.53
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Nucleic Acids Research (publishedVersion, cc-by-nc)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nd)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- HAL (submittedVersion, cc-by-nc)
- PubMed Central (submittedVersion, cc-by-nd)
- Funders
- Vallee Foundation
- Robert J. Kleberg, Jr. and Helen C. Kleberg Foundation
- Searle Scholars Program
- Institut National de la Santé et de la Recherche Médicale (ATIP-Avenir R21042KS/RSE22002KSA, R21042KS)
- Institut Pasteur
- Fondation Bettencourt Schueller
- National Institutes of Health
- National Key Research and Development Program of China (2022YFC3401500, 2022YFC2104800)
- National Institute of Allergy and Infectious Diseases (T32AI007334, R21AI168811, T32AI060537)
- MSDAVENIR
- H2020 European Research Council (PECAN 101040529)
- Topics
- Life Sciences › Immunology and Microbiology › Virology › Bacteriophages and microbial interactions
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › CRISPR and Genetic Engineering
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Bacterial Genetics and Biotechnology
- Keywords
- prokaryotes, bacteriophages, mobile genetic elements, cyclic nucleotide signaling, host-pathogen arms race, protein annotation
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