Here’s a thread on anti-interferon autoantibodies, viral infections, and human immunology. This is less a covid thread, and more an anti-covid thread, if anything… Summary: anti-IFN auto-Abs may be reflective of chronic inflammation, and may pre-exist in vulnerable groups at high levels. Presence in severe covid cases may therefore reflect basal immune variation which impacts covid, rather than a special covid-specific phenomenon.

The message is very simple. #BlackLivesMatter I'm grateful that others have put together resources like bit.ly/ANTIRACISMRESO…, which has helped me learn to be better. So You Want To Talk About Race by @IjeomaOluo and How To Be An Antiracist by @DrIbram have been amazing, and I'm looking forward to reading deeper.

The story about mitochondria being ~10° hotter than the rest of the cell, published @PLOSBiology a couple years ago (journals.plos.org/plosbiology/ar…) got some cool, albeit indirect, support recently @naturemethods… #Biophysics #CellBiology The original paper, which was mainly based on the temperature-dependent fluorescence of a mitochondria-targeting probe, was accompanied by a “Primer” (journals.plos.org/plosbiology/ar…) highlighting potential flaws and implications, a special sort-of-peer-review step by PLOS Biology.

Super neat story on how cellular quality control impacts the mutational landscape of proteins - beneficial mutations in DHFR during deep mutational scanning are totally altered dependent on cellular QC #Biophysics #Evolution biorxiv.org/content/10.110… Way to go! @KortemmeLab In an initial DMS experiment on DHFR, there were a large number (25% of all sequences!) of advantageous mutations spread across the whole protein. Reintroduction of QC protein Lon reduced the number of advantageous mutants and lowered average benefit of those mutations

A couple interesting bits of preliminary data on Langerhans cells and the huLangerin mouse used to study them. Effects of developmental absence of LCs on keratinocytes and T cells, and huLangerin-YFP labels some neurons (check your Cre mice!) #Genetics #Immunology First - effect of loss of LCs in the huLangerin-DTA mice - biorxiv.org/content/10.110…. Bulk RNA-seq showed changes in keratinocytes and dendritic epidermal T cells, including cell-type specific changes (e.g. loss of IL17 pathway in DETCs).

CYTOF analysis of human neutrophils - 7 populations with differing phagocytosis, ROS, and FACS-compatible surface marker phenotypes. Changes in distribution between healthy + melanoma patients. #Immunology #Cancer #Neutrophils biorxiv.org/content/10.110… Circulating neutrophil precursors, aged neutrophils, and a few populations of mature and immature neutrophils. Melanoma stage correlates with loss of dominant N2 (mature, ROS++, lowly phagocytic), and increase of N5 (immature, non-proliferative, ROS+, lowly phagocytic).

Platelets are sufficient to drive inflammasome up regulation and activation in myeloid cells, and are *necessary* for full IL-1 production biorxiv.org/content/10.110…. Another great platelet immunology preprint! @bernardo647 #Immunology #Platelets #Inflammasome Looking at malaria patients with thrombocytopenia shows decreased circulating IL-1 inversely correlating with platelet, but not total leukocyte, numbers, and depletion during PBMC prep almost eliminated IL-1 (and TNF) production in response to LPS!

IL11 signaling in fibroblasts in IPF biorxiv.org/content/10.110…. Follow up on a recent report on IL11 as a therapeutic target for IPF (stm.sciencemag.org/content/11/511…) - the original had good human data and some nice mouse models. @stuartacook1 #Immunology #Fibrosis This preprint dissects out the signaling with a floxed IL11RA1, conditionally deleted in fibroblasts. This drives basically the entire phenotype, and there are striking reductions in fibrosis in the fibroblast-KO mice. There’s also substantially lower inflammation.

Here's a #preprint that's got a wild statement in the introduction - biorxiv.org/content/early/… - seemingly reporting "accidental" pulmonary fibrosis in human patients treated with trans-resveratrol, but not reporting any of that data! Direct from the abstract: "We accidentally found that the continuous oral administration of trans-resveratrol (TR) at levels above the prescribed dose can induce PF within a certain period of time, and this model can be successfully replicated in mice"

@NatImmunol just published this comment, on “stealth” research - nature.com/articles/s4159…. I had high hopes for the topic, but unfortunately I think this comment reinforces damaging assumptions and attitudes towards publication and data accessibility, and needs addressing. (I’ll add that it draws clear inspiration from an earlier analysis of biotech “unicorns”, which @Dereklowe thoroughly responded to previously - blogs.sciencemag.org/pipeline/archi…)

A new paper in @CellCellPress describes a lymphocyte population expressing both rearranged TCR and BCR molecules, with a dominant public BCR clonotype that acts as an autoantigen in type 1 diabetes. Do we need to rewrite our textbooks? (hint: not yet) cell.com/cell/fulltext/… Very briefly, the paper describes a CD5+CD19+ population that is elevated in T1D patients and expresses both TCR and BCR - dual expressers, DEs. They do scRNAseq to show shared lineage genes in DEs with both T cell and B cells.

Here’s a bit of a dive into some interesting recent work on #PhaseSeparation in cells - focusing on the role of ATP as a protein stabilizer in cells, independent of its energy-providing function. It all starts with a paper in @ScienceMagazine from 2017, science.sciencemag.org/content/356/63…. This Science paper showed that in vitro, ATP had hydrotope activity - the ability to solubilize proteins, and dissolve protein aggregates or liquid phase droplets. This function occurred at millimolar concentrations of ATP, near normal cellular levels.

Here’s a wild #preprint on #immunology and #evolution @biorxivpreprint - lack of any detectable NK cells in naked mole rats, with a completely divergent immune distribution and novel cell types - biorxiv.org/content/10.110… Single-cell analysis of spleen and blood of naked mole rats reveals an inverted myeloid:lymphoid ratio compared to mice (i.e. naked mole rats have substantially more myeloid than lymphoid cells, while mice are the reverse).

New paper in @NatImmunol on TCR deorphanization caps off an exciting past couple months with a wide array of new methods! Goes well with a few in @NatureBiotech and @naturemethods. A quick breakdown of five new (and one new-ish) TCR-pMHC profiling methods… Starting with the most recent, nature.com/articles/s4159…. The authors express chimeric receptors fusing the MHC Class II extracellular domains to truncated TCR constructs, resulting in chimeric proteins that assemble with the CD3 complex (MCR2s).

Today marked a very interesting day in peer review experiments, which I’d like to focus on a bit - especially with @mbeisen coming on board as EIC in the midst of a very intriguing trial in author-centric publishing @eLife. As a quick reminder, @eLife ran a pilot program where they took an “author-centric” approach to peer review - any paper that passed the initial screening by editors was “guaranteed” to be published, regardless of reviews, if the authors desired.

Second, what is the role of the N-terminal domain in controlling localization of cGAS? We know the N-terminal domain is unstructured, involved in condensation, but not required for catalytic activity, and less conserved than the catalytic domain. Barnett show very clearly the N-terminal domain is binding PIP, and do the most thorough truncation analysis of the N-terminal domain to narrow down activity (membrane association and PI(4,5)P binding) to two amino acids in the N-terminal domain.

These three different stories (Barnett, Gentili, Volkman & Cambier), from @jkagan1, @NicolasManelLab, and @DanBStetson1, all look closely at localization of cGAS. Here’s how I, as an “armchair fan” of cGAS-STING only, understand all these data fitting together… First, these stories show cell biology is complicated. Digging through the methods shows how many things matter - different cell lines, use of nucleases during lysate preps, spin speeds, microscopy staining conditions, salt concentrations in nuclear extractions…

More cGAS localization work, showing membrane localization through PI(4,5)P binding, from @katbarnett3 in the @jkagan1 group, now online in @CellCellPress - cell.com/cell/fulltext/…. Very thorough sub cellular fractionation and microscopy showed cGAS was predominately bound to membranes, rather than in the soluble cytosolic fraction. This varies in a cell-type specific fashion, but there was consistently a membrane-bound fraction.

Paper 4 (and, effectively, an older paper 5): On nuclear cGAS, from @NicolasManelLab published in @CellReports, Gentili et al. cell.com/cell-reports/f… I’ll take a step back to reflect on nuclear cGAS. @DanBStetson1 gave a talk last year at Yale on what came out as this phenomenal #preprint @biorxivpreprint, Volkman and Cambier et al - biorxiv.org/content/early/…

cGAS-STING work continues to boggle the mind - flurry of new papers in the last two weeks branching the field in new directions. I’ll try for quick (not really) takes… #cGAS #microbiology #Immunology #Inflammation @nature @biorxivpreprint @NatureMicrobiol @CellReports Paper 1: @aaronwhiteley et al writing in @nature - nature.com/articles/s4158…. cGAS-like nucleotidyltransferases in bacteria (CD-NTases) synthesize a wide range of cyclic dinucleotides (CDNs) - and more, including trinucleotides (CTNs?)!

And then this super interesting paper @nature on viral evasion of cGAS-STING signaling through nucleases that cleave cGAMP - nature.com/articles/s4158…. #Immunology #Virology Screening for cGAMP cleavage activity uncovered poxvirus immune nucleases (poxins) - important for evasion of cGAS-STING mediated immunity in cells. Great structural biology showing mechanism, and then phylogenetics through poxvirus family and into metazoans!