Find more here 10/fin.

This was the result of tenacious work and deep thinking by Cason King, and offers a legacy that reflects who he was as a scientist. I thank other lab members and our collaborators in the labs of Judy Smith and @LangloisLab, and @BWFPATH for supporting risky science. 9/10.

Main takeaways:.• sensing self-DNA amplifies antiviral responses to influenza virus.• TREX1 supports infection by moderating DNA sensing .• viral-driven CRISPRa enables fitness-based screening to probe new areas of the virus:host interface (works for other viruses too) 8/10.

Our work revealed that TREX1 acts at the top of the cGAS/STING cascade, degrading DNA and moderating activation of innate immunity. As a consequence, TREX1 inadvertently aids influenza virus replication (and other viruses), hence its identification as a hit in our screen. 7/10.

TREX1 is a DNA exonuclease the clears cytoplasmic DNA. Reinforcing the work of others, we showed that infection causes release of mtDNA into the cytoplasm of infected cells. This triggers the cGAS/STING pathway to amplify innate immune responses. 6/10.

A key advantage is that the sgRNA is encoded in the viral genome, and the sequence of the sgRNA tells you what cellular gene was activated. So all we need to do is sequence viral genomes before and after selection to find our "winners." One of our top hits was TREX1. 5/10.

Cason King took the reins at this point. He created a massive library of influenza viruses targeting every gene in the human genome, and then let these viruses fight it out. Viruses activating pro-viral host gene quickly dominate the population. 4/10

By directing changes to host gene expression, the virus alters the cellular landscape to affect its own fitness. (Note that this is done with a high degree of safety as it only works in cells that already express the CRISPRa machinery.) 3/10.

We turned to CRISPRa, a technique where a mutant Cas9 scaffolds recruitment of transcriptional activators to the targeted gene. We then engineered influenza virus to encode the sgRNA that programs Cas9 to the gene we want to activate. 2/10.

We love genetic approaches to define virus:host interactions. Knockout screens are powerful, but. technical constraints limit what you can find. Could we devise a screen where viral fitness pinpoints the key regulators of replication? (spoiler - yes 1/10.

Bittersweet final lab meeting with Jordan Ranum (white shirt). Jordan is off to med school at UW Madison. He joined as an undergrad and stayed as a scientist. Watch out for his amazing project on defective viral genomes that is about to drop.

It's been a busy work for the lab. Thomas (holding 🍾) passed his @UWMadisonMDTP qualifying exam with aplomb. Very excited to see him tackle his project as a dissertator. Congrats Thomas.

Excited to announce the successful thesis defense by newly minted Dr. @graceschaack (seen riding her thesis gift, a T-Rex). Great public presentation and closed-door defense. Super proud to have her as a lab alumna, and returning to the clinic to complete her MD. Congrats!

RT @CMB_UWMadison: Congratulations to CMB Alums, Mitch Ledwith and Dan Tremmel, the 2022 Raymond L. Erikson Exceptional Thesis Award recipi….

RT @PLOSBiology: Studying how #influenza virus engages the cellular environment, @bakerlabLBRI @MehleLab &co find that host cells use #Alte….

When is an antiviral protein not antiviral? It's all about context. Cason summarized our current thinking about the subtle balance between pro- and antiviral activities. Free access for 50 days

The fun begins at #ASV2022. Come see the exciting work from the lab with presentations Saturday by Jordan (W5-12), Sunday by Cason (W16-6) and Grace (W16-9), and Tuesday by Andy. All lab members are available to offer expert, local advice on best places for food, coffee and beer.

RT @NatureComms: Influenza A virus undergoes compartmentalized replication in vivo dominated by stochastic bottlenecks. @kaaamato @mehlelab….

Our NSV talks highlighted some of the fun projects in the lab. If you found them as interesting as we do, and you're looking for a postdoc, reach out. We're looking for someone to join our team. See pic for details. Drop a line to chat, or find Andy at #NSV2022.

Fantastic Suppressing and Conquering session and talk by @casonthemason at #NSV2022. Be sure to find him to ask about his favorite dinosaur.