Daniel Fisch

Daniel Fisch

@danielhfisch.bsky.social

Group Leader at the Gulbenkian Institute for Molecular Medicine (GIMM) Innate Immunology, Macrophages & Toll-Like Receptors πŸ”¬πŸ‘¨β€πŸ”¬

332 followers656 following47 posts

Daniel Fisch
@danielhfisch.bsky.social

Thank you for inviting me to join @gimminstitute.bsky.social! Exciting times ahead!

GIMM Institute@gimminstitute.bsky.social

Welcome to GIMM, @danielhfisch.bsky.social! πŸ’œ As Group Leader in Innate Immunity, Daniel studies how our immune system detects and responds to infections. πŸ”¬ He looks forward to building his team and collaborating with GIMM’s scientific community.

Daniel Fisch
@danielhfisch.bsky.social

After Germany, the UK, France and the US, it feels wonderful to build my scientific home back in Europe. πŸ§ͺπŸ‡΅πŸ‡Ή Now the exciting part begins...building a team and chasing big questions together. Can't wait for the discoveries ahead!

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Daniel Fisch
@danielhfisch.bsky.social

I want to thank all my colleagues from the Kagan lab for making this work possible and especially @jkagan1.bsky.social for his support of my postdoc training and mentorship for the past 5 years! Thanks to all funders supporting this work! (NIH, HFSP, EMBO, HRIA King Trust, CRI Irvington).

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Daniel Fisch
@danielhfisch.bsky.social

If long-lived myddosomes sustain inflammation, disrupting them should stop it. Conversely, MyD88 oligomerization inhibitors (MPP, TSI-13-57) dissolved already-formed myddosomes in cells. We detected for the first time native myddosomes in mice, which could be shut down by the same inhibitors.

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Daniel Fisch
@danielhfisch.bsky.social

We could separate the role of TRAM in the TRIF-arm from its role in the MyD88-arm of TLR signaling based on its localization. Forcing TRAM to the plasma membrane restores myddosome release but abolishes IFN. Endosome-restricted TRAM does the opposite.

Daniel Fisch
@danielhfisch.bsky.social

We then reconstituted the release mechanism in vitro with three TIR domains. We found that TIRAP restrains MyD88 self-assembly and TRAM relieves that restraint. The purified domains are sufficient to reproduce the behavior seen in cells.

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Daniel Fisch
@danielhfisch.bsky.social

Across bacterial infections, TRAM was required for IL-6 but not TNFΞ± production. In infected cells MyD88 again remained at the plasma membrane when TRAM was absent.

Daniel Fisch
@danielhfisch.bsky.social

For releasing myddosomes TRAM acts alongside TIRAP in PI(4,5)P2-rich plasma-membrane microdomains. TRAM mutants, chimeras and CRISPR-Activation showed that the local TIRAP:TRAM ratio, rather than the abundance of either protein, determines whether myddosomes are released.

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Daniel Fisch
@danielhfisch.bsky.social

The release is what makes TLR signaling last. While WT macrophages sustain NF-ΞΊB for hours, TRAM-deficient cells produce a single peak and then terminate signaling early.

Daniel Fisch
@danielhfisch.bsky.social

This reflects in transcription: Primary response genes are induced without TRAM, but secondary response genes (e.g. IL-6, IL-12) are not. By RNA-seq, TRAM-deficient macrophages return to baseline by 6 h while WT cells remain activated.

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Daniel Fisch
@danielhfisch.bsky.social

Without TRAM, MyD88 does not move. Proto-myddosomes still nucleate at the plasma membrane but are never released, and no cytosolic myddosomes form. Other adaptor knockouts behaved as expected; Ξ”TRAM was unique in that myddosome assembly starts but maturation fails.

Daniel Fisch
@danielhfisch.bsky.social

Using minute-by-minute co-IPs we found that MyD88 first binds TLR:TIRAP (proto-myddosome), TRAM then releases MyD88 so it can recruit IRAK2/4 and TRAF6 (mature myddosome). Without TRAM, MyD88 stays bound to TLR:TIRAP for hours.

Daniel Fisch
@danielhfisch.bsky.social

We began the study by exploring which cells actually respond to TLR-ligands? Using a side-scatter-based sort we separated macrophages into myddosome-containing responders and myddosome-free bystanders. Only responders switch on the TLR gene program.

Daniel Fisch
@danielhfisch.bsky.social

To find what builds a myddosome, we performed a genome-wide CRISPR screen, sorting for cells with no myddosomes and no NF-ΞΊB activity. We obtained one very unexpected hit: TRAM (Ticam2), the adaptor long exclusively assigned to the MyD88-independent TRIF pathway.

Daniel Fisch reposted

Ben Hale
@benhale.bsky.social

Congrats to Samira Schiefer on her new paper in Science Advances! We analysed 70 natural human IFNB1 variants & found both loss- & gain-of-function IFNΞ² proteins, revealing unexpected diversity in antiviral immunity. Great effort with Dave Jones & Florence Kwaschik! www.science.org/doi/10.1126/...

science.orgFunctional diversity of natural human IFNB1 variants in innate immunityHuman interferon-Ξ² (IFN-Ξ²), a type I IFN, is critical for effective innate immunity and is also an approved disease-modifying therapeutic. While genetic variations in several components of the type I ...

Daniel Fisch reposted

Florian Wollweber
@florianwollweber.bsky.social

Exciting news! Our @erc.europa.eu StG project ARCHAEAOLOGY got funded πŸŽ‰ We’ll combine cryoET/EM, ExM & spatial omics to explore the subcellular organization of Asgard archaea. Job ads coming soon! 🦠 ❄️ πŸ”¬ #TeamTomo #ArchaeaSky #MicroSky

EMBL@embl.org

Congratulations to @florianwollweber.bsky.social, the recently appointed Group Leader at EMBL Grenoble, who received an ERC Starting Grant worth approximately €2 million to investigate the origins of eukaryotic cell complexity. bit.ly/4gNwEBk

Daniel Fisch reposted

Carl Zimmer
@carlzimmer.com

The lab is a mysterious place--where some people have "magic hands," and some experiments just won't work. Here's my story about the unspoken knowledge of science, and the struggle to share it. Gift link: nyti.ms/3UccF7Z

Daniel Fisch reposted

PLOS Biology
@plosbiology.org

Graphing and statistically analyzing data is challenging without coding expertise. This Community Page by @avishenoy.bsky.social introduces grafify online, a free, browser app for generating publication-quality graphs and performing statistical tests and comparisons. πŸ§ͺ #AcademicSky plos.io/3RpUg6E

Daniel Fisch reposted

GIMM Institute
@gimminstitute.bsky.social

Apply until May 3rd, 2026 Join GIMM for a PhD in Biology & Biomedicine (Jan 2027). 🧬 We advance research addressing complex biological questions while providing the foundational and professional skills required for multiple career paths. πŸ”— gimm.pt/education-an...

Daniel Fisch reposted

Caetano Reis e Sousa
@reisesousalab.bsky.social

Delighted that this study is finally out @embojournal.org. A detailed analysis of how DNGR-1/CLEC9A signals to promote cross-presentation of dead cell-associated antigens yet does not activate dendritic cells. www.embopress.org/doi/full/10....

embopress.orgDNGR-1 signalling limits dendritic cell activation for optimal antigen cross-presentation | The EMBO JournalimageimageDNGR-1 (CLEC9A) is a C-type lectin receptor of type-1 conventional dendritic cells (cDC1s) with an important role in cross-presentation of dead cell antigens. This study explores how it equips cDC1s with the ability to cross-present such ...

Daniel Fisch reposted

Matteo Carandini
@carandinilab.net

Europe's MSCA postdoctoral fellowships are now attracting many researchers who would have gone to the US. So the payline has dropped below 10% (~1,600 fellowships to 17k applicants). Super tough situation. One more reason to double the next Horizon budget, as proposed by the EU Commission.

Tom Emery@drtomemery.bsky.social

Applications for MCSA are up 64%! 50% now come from outside the EU. Trump effect? The European Research market just got a hell of a lot more crowded. EU should turn on the tap marie-sklodowska-curie-actions.ec.europa.eu/news/msca-po...

marie-sklodowska-curie-actions.ec.europa.euMSCA Postdoctoral Fellowships 2025 receives record number of 17,058 proposalsThis year’s annual MSCA Postdoctoral Fellowships call has attracted considerable interest from the research community with 17,058 proposals submitted.

Daniel Fisch reposted

Ivan Zanoni
@lozanzi.bsky.social

#InflammasomePower! πŸ’₯New paper alertπŸ’₯ How is NLPR3 primed & activated in chronic non-communicable inflammatory diseases? With @oceanedufies.bsky.social &co we show that chronic exposure to oxPAPC drives NRF2 activation that primes & activates NLRP3 sustaining #atherosclerosis in mice & humans! πŸ‘‡πŸ‘‡πŸ‘‡

biorxiv.orgChronic sensing of host-derived lipids is an all-in-one signal that primes and activates NLRP3.Activation of the NLRP3 inflammasome leads to the production of bioactive interleukin (IL)-1Ξ² fostering atherosclerosis. The current dogma is that NLRP3 must be first primed by microbial stimuli, know...

Daniel Fisch reposted

Jonathan Kagan
@jkagan1.bsky.social

meta-PAMPs: A new class of immunostimulatory molecules that control the ability of bacterial factors to operate as PAMPs. Jordan Jastrab reveals that wall teichoic acid (WTA) is a key regulator of inflammasomes and interferons during infection. www.biorxiv.org/content/10.1...

biorxiv.orgWall teichoic acid is required for DNA-triggered innate immune receptor activation by Staphylococcus aureusReceptors that stimulate inflammation are commonly activated by ligands that are buried within microbial cells. The mechanisms that facilitate immunostimulatory ligand release from microbes during inf...

Daniel Fisch reposted

Jordan Jastrab
@jordanjastrab.bsky.social

Thrilled to share my work from the @jkagan1.bsky.social lab! TLDR: O-acetylation and wall teichoic acid compete for space on S. aureus peptidoglycan. This competition regulates DNA release, and thus immune receptor activation, during infection! www.biorxiv.org/content/10.1... #microsky #immunosky

biorxiv.orgWall teichoic acid is required for DNA-triggered innate immune receptor activation by Staphylococcus aureusReceptors that stimulate inflammation are commonly activated by ligands that are buried within microbial cells. The mechanisms that facilitate immunostimulatory ligand release from microbes during inf...

Daniel Fisch reposted

Thiago Carvalho
@cyrilpedia.bsky.social

Tools: "Here, we developed a class of highly sensitive genetically encoded STAT biosensors, termed STATeLights, which allowed direct and continuous detection of STAT activity in live cells with high spatiotemporal resolution." www.nature.com/articles/s41...

nature.comReal-time visualization of STAT activation in live cells using genetically encoded biosensors - Nature Chemical BiologyThe signal transducer and activator of transcription (STAT) family proteins are attractive drug targets but tools to monitor their activation are lacking. Now, STAT biosensors have been developed for ...

Daniel Fisch reposted

Dr Rebecca Coll
@colllab.bsky.social

So excited that this study is now online! It's been a pleasure to work with BioAge Labs and our collaborators on this story. We characterise a new class of #NLRP3 inhibitors with translational potential for so many inflammatory diseases.

Journal of Experimental Medicine@jem.org

#NLRP3 is a target for antiinflammatory therapies & can be inhibited by the tool compound MCC950. Wilhelmsen, @colllab.bsky.social et al characterize new small-molecule inhibitors, BAL-0028 & BAL-0598, that have a distinct mechanism of action & binding site. rupress.org/jem/article/... #Inflammasome

Daniel Fisch reposted

Jonathan Kagan
@jkagan1.bsky.social

Everything you wanted to know about oxidized lipids & immunity, in one review. We explain how oxidized lipids impact inflammation, dendritic cells, anti-tumor immunity and more. Kudos to Joon Choi for his exceptional work. royalsocietypublishing.org/doi/10.1098/...

royalsocietypublishing.orgOxidized phospholipid damage signals as modulators of immunity | Open BiologyDamage-associated molecular patterns (DAMPs) are self-derived molecules released during tissue damage that influence immune responses. Phospholipids, essential to cell membranes and lung surfactants, ...

Daniel Fisch reposted

Jonathan Kagan
@jkagan1.bsky.social

MyD88 cell biology explored in yeast. The fantastic @VictorJCid and colleagues reveal an unexpected variety of organelles MyD88 can bind in budding yeast. Kudos to all authors on this exciting finding. link.springer.com/article/10.1...

link.springer.comMyD88 polymerization and association to cellular membranes in a yeast heterologous model - Cellular and Molecular Life SciencesMyD88 is a key mediator of Toll-like receptor (TLR) signaling, orchestrating the innate immune response upon stimulation by pathogen-associated molecular patterns (PAMPs). Structurally, MyD88 consists...

Daniel Fisch reposted

Ricardo Henriques
@henriqueslab.bsky.social

🚨Join us! We're soon opening 3 postdoctoral positions in #AIDrivenBiology. Seeking biologists (especially microbiology and infection biology), computer scientists, and microscopy developers. Ideal candidates are those eager to use or develop next-gen tech for cell biology. Get in touch (DM/email)