🧬 Metabolic arms race continues!
We discovered a new NAD⁺-depleting bacterial immune system aRES and phage enzymes that overcome it.
Our preprint is out: www.biorxiv.org/content/10.6...

Preprint: We discovered phage proteins that sequester diverse immune signaling molecules, including cUMP, cCMP, and N7-cADPR

The first viral sponges to inhibit Pycsar and type IV Thoeris

Congrats to talented leading author Romi Hadary! Read her thread to learn more about our findings

New pre-print from Doudna lab members @erinedoherty.bsky.social & @jnoms.bsky.social ✨

Here we explore how recurrent adaptation of a single anti-defense protein fold enables evasion of distinct immune systems.

Divergent viral phosphodiesterases for immune signaling evasion Cyclic dinucleotides (CDNs) and other short oligonucleotides play fundamental roles in immune system activation in organisms ranging from bacteria to humans. In response, viruses use phosphodiesterase...

Excited to share our new preprint co-led by @jnoms.bsky.social!

Here we reveal an exceptional diversity of viral 2H phosphodiesterases (PDEs) that enable immune evasion by selectively degrading oligonucleotide-based messengers. This 2H PDE fold has evolved striking substrate breath & specificity.

A widespread family of viral sponge proteins reveals specific inhibition of nucleotide signals in anti-phage defense Chang et al. discover anti-CBASS 4 (Acb4), a family of viral sponges that inhibits bacterial immunity by sequestering nucleotide immune signals. Acb4 homologs in phages that infect hosts across all ma...

The beautiful, ever-expanding universe of viral proteins targeting nucleotide immune signals!

Paper by @reneechang.bsky.social in @cp-molcell.bsky.social on a nucleotide sponge www.cell.com/molecular-ce...

and preprint by @doudna-lab.bsky.social on viral nucleases www.biorxiv.org/content/10.1...

Strengthening phage resistance of Streptococcus thermophilus by leveraging complementary defense systems - Nature Communications A study by Leprince et al. shows the effectiveness of Streptococcus thermophilus defense systems against dairy phages, their synergy with CRISPR-Cas, and the absence of fitness cost under lab or indus...

😮 Cool work from Sylvain Moineau

#phage #phagesky

www.nature.com/articles/s41...

Hypermutable hotspot enables the rapid evolution of self/non-self recognition genes in Dictyostelium Cells require highly polymorphic receptors to perform accurate self/non-self recognition. In the amoeba Dicytostelium discoideum, polymorphic TgrB1 & TgrC1 proteins are used to bind sister cells and e...

I'm excited to announce our new biorxiv preprint, wherein we investigate the evolution of the weirdest genetic locus I've ever seen! Behold the tgr genes of the social amoeba, which mediate self/non-self discrimination during facultative multicellularity 🐅 🧵 1/
www.biorxiv.org/content/10.1...

Fantastic results from the very talented @romihadary.bsky.social et al. on viral counter-defence sponges!! 🧽🦠

Manipulation of the nucleotide pool in human, bacterial and plant immunity - Nature Reviews Immunology Modification of the nucleotide pool is emerging as key to innate immunity in animals, plants and bacteria. This Review explains how immune pathways conserved from bacteria to humans manipulate the nuc...

We wrote a review on the free nucleotide pool as a central playground in human, bacterial, and plant immunity – now out in Nature Reviews in Immunology

www.nature.com/articles/s41...

Was fun to write this piece with Dina Hochhauser!

Here is a thread to explain the premises

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Manipulation of the nucleotide pool in human, bacterial and plant immunity - Nature Reviews Immunology Modification of the nucleotide pool is emerging as key to innate immunity in animals, plants and bacteria. This Review explains how immune pathways conserved from bacteria to humans manipulate the nuc...

Read my review with @soreklab.bsky.social on the nucleotide pool as a central playground in antiviral immunity across humans, bacteria and plants! 🧍‍♀️🦠🌿

& how viruses overcome these nucleotide-based immune mechanisms 🗡️

www.nature.com/articles/s41...

It was such a pleasure to work on this wonderful project with the talented @nitzantal.bsky.social !

Recurrent acquisition of nuclease-protease pairs in antiviral immunity Antiviral immune systems diversify by integrating new genes into existing pathways, creating new mechanisms of viral resistance. We identified genes encoding a predicted nuclease paired with a trypsin...

Excited to finally share this work!
We noticed a pair of genes - a nuclease and a protease - shuffles between antiviral systems. We show how proteolysis activates the nuclease, triggering defense in known and unknown immune contexts.
tinyurl.com/2uwwy4ty

Filamentous cheater phages drive bacterial and phage populations to lower fitness Many bacteria carry phage genome(s) in their chromosome (i.e., prophage), and this intertwines the fitness of the bacterium and the phage. Most Pseudomonas aeruginosa strains carry filamentous phages ...

Our new preprint by @nanamikubota.bsky.social shows that P. aeruginosa, and likely many other bacteria carrying filamentous prophages (like V. parahaemolyticus), risk being exploited by these phages in a runaway process that reduces fitness of both host and virus. www.biorxiv.org/content/10.1... 🧵

END nucleases: Antiphage defense systems targeting multiple hypermodified phage genomes Prokaryotes carry clusters of phage defense systems in defense islands that have been extensively exploited bioinformatically and experimentally for discovery of immune functions. However, little effo...

We've identified a group of nucleases that can target multiple phages with hypermodified DNA, using a sensor domain present across many domains of life. We’ve even used this as a tool to find phages with hypermodified DNA! Really thankful to all the co-authors who have been such great help!

Interested in phage defenses that natively block lytic phage used in therapies?

Or do you want to figure out if a phage has a modified genome?

Meet the END-nucleases, an enzyme family that can broadly restrict phages with many diverse modifications. From talented post-doc Wearn-Xin Yee!

A phage-encoded counter-defense inhibits an NAD-degrading anti-phage defense system Author summary Bacterial viruses (bacteriophages or phages) are widespread and abundant across the planet. Bacteria have a variety of immune systems, often found on mobile genetic elements, to combat ...

Excited to share that my first first author paper from grad school is up now at PLOS Genetics @plos.org! dx.plos.org/10.1371/jour...

A miniature CRISPR-Cas10 enzyme confers immunity by an inverse signaling pathway Microbial and viral co-evolution has created immunity mechanisms involving oligonucleotide signaling that share mechanistic features with human anti-viral systems. In these pathways, including CBASS a...

Preprint alert! ✨ In this project that I co-led with @benadler.bsky.social, we show that a miniature CRISPR-Cas10-like enzyme, mCpol, uses a novel inverse signaling mechanism to prevent the spread of viruses that attempt immune evasion by depleting host cyclic nucleotides.

Check it out:

Big Fantastic Virus Database (BFVD) version 2 improves 31% of predictions through 12 ColabFold recycles. PAEs and MSAs now also available for download and in the webserver.
🌐https://bfvd.foldseek.com
💾https://bfvd.steineggerlab.workers.dev/
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BFVD has been updated to version 2! Rachel improved the accuracy of viral structure predictions by running 12 recycles of ColabFold (AlphaFold2). In the latest database, over 60% of the predicted structures are now high quality. Also, we provide the PAE JSON files for each predictions.

A minimal CRISPR polymerase produces decoy cyclic nucleotides to detect phage anti-defense proteins www.biorxiv.org/content/10.1101/2025.03....

Structural basis of antiphage defense by an ATPase-associated reverse transcriptase www.biorxiv.org/content/10.1101/2025.03....

Protein-primed DNA homopolymer synthesis by an antiviral reverse transcriptase Bacteria defend themselves from viral predation using diverse immune systems, many of which sense and target foreign DNA for degradation. Defense-associated reverse transcriptase (DRT) systems provide...

Hello BlueSky! Inaugural post here from the Sternberg Lab. We're excited to share our latest work, in which we teamed up with the @WiedenheftLab to study how DRT9 reverse transcriptases provide antiviral immunity. Here’s what we found: www.biorxiv.org/content/10.1...

Alt : Structure of the apo Lamassu protein complex. Schematic model of the active LmuA tetramer nuclease (top right). Lamassu icon (top left).

Glad to share the work of @yli18smc.bsky.social and co on Lamassu, a bacterial defense system related to Rad50/Mre11 (RM). While RM carefully trims DNA ends for repair, Lamassu chops up the host chromosome. Our study reveals how it is regulated to minimize damage, activating only during infection.

Side view of the structure of a monomer of type II Wadjet.

Happy to share the beautiful structure of a Wadjet SMC complex by @roisnehamelinf.bsky.social, with support from the DCI and @drhonsworth.bsky.social ! This is a type II Wadjet with unique characteristics including a tandem KITE subunit, distinct coiled coil architecture and a deviant hinge.

Functional Metagenomic Selections for Phage Defense

My lab’s first preprint!

We used functional metagenomics to identify phage defenses in human and soil microbiomes. We scaled these selections while maintaining accuracy, enabling us to examine 9 habitats for defense elements against 7 phages.

www.biorxiv.org/content/10.1...

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we recently found some really neat RNA-guided DNA-cutting systems in phages. Despite remarkable similarities to CRISPR systems, including encoding guide RNAs in arrays, they appear entirely evolutionarily distinct (but definitely related to snoRNAs 🤓)
We decided to call them TIGR-Tas systems 🐯

Pseudomonads coordinate innate defense against viruses and bacteria with a single regulatory system www.biorxiv.org/content/10.1101/2025.02....

A prophage-encoded anti-phage defense system that prevents phage DNA packaging by targeting the terminase complex www.biorxiv.org/content/10.1101/2025.02....

CRISPRi-ART enables functional genomics of diverse bacteriophages using RNA-binding dCas13d - Nature Microbiology Leveraging RNA-targeting dCas13d enables selective interference with phage protein translation and facilitates measurement of phage gene fitness at a transcriptome-wide scale.

It is finally out!

Muntathar Al-Shimary, @doudna-lab.bsky.social , @cresslab.bsky.social and I present a gene knockdown tool that works in diverse bacteriophages: CRISPRi through antisense RNA Targeting (CRISPRi-ART)!

Check it out @naturemicrobiol.bsky.social
www.nature.com/articles/s41...