I'm hiring a postgrad, a great position for someone looking for a few years of training before applying to grad school! Come join us and learn microbiology, protein purification, and mucosal immunology: postdocs.yale.edu/posts/2026-0...
The Trojan Horse is real, and itβs microscopic! π΄π¦
Our paper is out today in @cellcellpress.bsky.social!
We discovered that deltaviruses physically hide INSIDE helper viruses to sneak into new cells. And to prove it, we had to image them from every angle. π§΅π
www.sciencedirect.com/science/arti...
π¨Preprint! Happy to share the research from my PhD βGenome delivery of a contractile tailed phage and its superinfection exclusion mechanismβ. We use cryoEM to study the genome ejection of the phage T4, revealing how the tape measure protein regulates the process.
www.biorxiv.org/content/10.6...
Finally, huge thanks to Philip and all the current and former members of the Kranzusch lab β it has been incredibly fun talking about this project with you all!
If these questions are interesting to you, we are always looking for motivated scientists to join our new lab at University of Utah :)
This was an exciting step in understanding the mechanism of CD-NTase activation but many questions remain: Structurally, how does loop cleavage catalyze immune signal synthesis? What are Cap2 and Cap3 doing in this operon? What are the specificity determinants to detect diverse phage proteases?
We know other operons defend against T4 β does loop cleavage activate those CD-NTases? We found similar loops in ~24% of CD-NTases, including DncV! Remarkably, these enzymes are also activated by proteinase K treatment, demonstrating proteolysis is a widespread mechanism of CBASS activation.
Does this loop matter in vivo? We performed alanine scanning of the CdnG activation loop and found residues required for defense against T4 Ξacb1/acb2. These same residues are required for activation of CBASS toxicity by the T4 gp21, supporting direct activation of CBASS immunity by T4 protease
Mutation of the trypsin sites within this loop prevented trypsin-dependent activation, clearly demonstrating that cleavage of this disordered loop causes CdnG activation. Proteinase K treatment still triggered 3ΚΉ2ΚΉ-cGAMP synthesis, so we didnβt simply kill the enzyme with the trypsin mutations.
Where are proteases cleaving CdnG? We used AlphaFold3 to model CdnG and found a disordered loop that was suspiciously located in the region that is responsible for DNA-dependent activation of human cGAS, suggesting a role in activation.
Does T4 gp21 activate CdnG directly? gp21 cleaves itself, making its purification in the active form difficult. So we performed a somewhat crazy experiment and modeled gp21 activity in vitro by treating CdnG w/ a panel of proteases. Remarkably, this was sufficient to trigger 3ΚΉ2ΚΉ-cGAMP synthesis!
But what is the signal that turns CdnG on? In T4 (and many other phages), capsid maturation is regulated by an essential protease that cleaves capsid components. We took a leap of faith and asked whether the T4 prohead protease (gp21) could be sufficient to activate CBASS toxicity β and it is!
We first reconstituted phage sensing in vitro by mixing lysates from cells expressing CBASS and lysates from cells infected with T4 Ξacb1/2 and monitored CdnG activation using a Cap5 nuclease biosensor assay. CBASS turns on late during infection, coincident with T4 capsid maturation
We focused on the phage T4, which encodes two anti-CBASS (Acb) proteins that target CBASS nucleotide signals. Removal of Acb1+2 makes T4 highly susceptible to a CBASS operon with a clade G CD-NTase, demonstrating that Acb1/2 proteins βmaskβ an unknown factor that activates CBASS signaling.
CBASS is a cyclic nucleotide-based antiviral system in bacteria that is related to cGAS-STING signaling in animals. One of the big questions is how CBASS is activated during phage infection? We made some progress on this during my final year in the Kranzusch lab.
www.biorxiv.org/content/10.6...
Out today: We discovered new viral proteins that target immune signaling molecules, solely based on their AlphaFold-predicted shapes
www.science.org/doi/10.1126/...
Congrats Nitzan Tal and coauthors! Thank you Kranzusch lab for the fun collaboration!
Linking below previous thread on our findings
π’Preprint out!
Excited to share my final work from the @soreklab.bsky.social!
We mined phage dark matter using structural features shared by anti-defense proteins (viral tools that help phages bypass bacterial immunity) to guide discovery.
Found 3 new families targeting immune signaling!
In our latest work, we characterise the Tmn defence system. We reveal plasmolysis as a new way to block phage infection, dramatically reducing secondary infections.
A 5-hydroxymethylcytosine DNA glycosylase provides defense against T-even bacteriophages https://www.biorxiv.org/content/10.64898/2026.02.25.707755v1
CBASS limits bacteriophage production while maintaining cell viability in Pseudomonas aeruginosa https://www.biorxiv.org/content/10.64898/2026.02.24.707611v1
Excited to share our preprint exploring the structural, biochemical and in vivo properties of DRT7/UG10 reverse transcriptases which produce dsDNA using their primase and polymerase activities and provide broad-spectrum antiphage defense! www.biorxiv.org/content/10.6...
π«³ For c-di-AMP aficionados: Structural mechanism and inhibitor discovery for DhhP, a Borrelia burgdorferi cyclic di-AMP phosphodiesterase with an Fe/Mn bimetallic center!
In
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Structure www.cell.com/structure/fu...
@structure
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Happy by a recent biorxiv pre-print about DARNA (PD-T7-3) anti-phage defense system. This system is activated by binding to ssDNA, presented by phage SSB, to cleave tRNA in the anti-codon loop.
www.biorxiv.org/content/10.6...
I am incredibly honored to receive this recognition from the Michelson Medical Research Foundation for our work on innate immune signaling.
www.michelsonmedicalresearch.org/news/michels...
The giant viruses surprised us at almost every turn of this project, but ultimately led us down a very rewarding path. Happy to share this work is now available online π§ͺ
Max Fels @mfels.bsky.social from our lab discovers giant DNA viruses that infect amoeba encode eIF4E and the entire suite of 4F complex proteins to control mRNA translation, including beautiful crystal structures of viral 4E bound to modified mRNA 5' caps:
www.cell.com/cell/fulltex...
New online! The paradox of immune systems conservation between prokaryotes and eukaryotes
Chemical inhibition of a bacterial immune system
Small molecules inhibit type II Thoeris anti-phage systems from diverse bacteria. One compound, IP6C, improves phage-therapy against P. aeruginosa & is effective against Thoeris in polymicrobial communities
www.cell.com/cell-host-mi...
