bims-nimamd Biomed News
on Neuroimmunity and neuroinflammation in ageing and metabolic disease
Issue of 2024–06–02
thirty-two papers selected by
Fawaz Alzaïd, Sorbonne Université
  1. Cells dispose of cytoplasmic mitochondrial DNA by nucleoid-phagy.
  2. The chromatin landscape of pathogenic transcriptional cell states in rheumatoid arthritis.
  3. Glucose restriction in antiviral defence.
  4. Long-read sequencing for 29 immune cell subsets reveals disease-linked isoforms.
  5. It's time for your performance review.
  6. 'Smart' antibiotic can kill deadly bacteria while sparing the microbiome.
  7. How I overcame my stage fright in the lab.
  8. Systematic decoding of cis gene regulation defines context-dependent control of the multi-gene costimulatory receptor locus in human T cells.
  9. Germline variants alter immune surveillance.
  10. Germline-targeting immunogens guide bnAb development.
  11. Development of a novel non-invasive biomarker panel for hepatic fibrosis in MASLD.
  12. Pancreatic beta-cell IL-22 receptor deficiency induces age-dependent dysregulation of insulin biosynthesis and systemic glucose homeostasis.
  13. Living bioelectronics resolve inflammation.
  14. Alternative protein sources: science powered startups to fuel food innovation.
  15. Cytokine polarized, alternatively activated bone marrow neutrophils drive axon regeneration.
  16. Hippo-YAP/TAZ signalling coordinates adipose plasticity and energy balance by uncoupling leptin expression from fat mass.
  17. Rab30 facilitates lipid homeostasis during fasting.
  18. Metabolism of L-arabinose converges with virulence regulation to promote enteric pathogen fitness.
  19. NG2 glia protect against prion neurotoxicity by inhibiting microglia-to-neuron prostaglandin E2 signaling.
  20. Natural killer cells show their cancer-fighting worth.
  21. AgRP neuron cis-regulatory analysis across hunger states reveals that IRF3 mediates leptin's acute effects.
  22. Unfolding emergency calls stress granules to the ER.
  23. Inflammation causes insulin resistance in mice via interferon regulatory factor 3 (IRF3)-mediated reduction in FAHFA levels.
  24. Autistic people three times more likely to develop Parkinson's-like symptoms.
  25. A targeted single mutation in influenza A virus universal epitope transforms immunogenicity and protective immunity via CD4+ T cell activation.
  26. A snapshot into the transcriptomic landscape of apoptosis and ferroptosis in cancer.
  27. Enhancing prime editing in hematopoietic stem and progenitor cells by modulating nucleotide metabolism.
  28. Novel somatic mutations in blood driving age-related clonal hematopoiesis.
  29. CLUH maintains functional mitochondria and translation in motoneuronal axons and prevents peripheral neuropathy.
  30. I study artefacts left in prehistoric caves.
  31. Stiff tumours exhaust T cells.
  32. 13C metabolite tracing reveals glutamine and acetate as critical in vivo fuels for CD8 T cells.
  1. Nat Cell Biol. 2024 May 29.
    Cells dispose of cytoplasmic mitochondrial DNA by nucleoid-phagy.
      
    DOI:  https://doi.org/10.1038/s41556-024-01421-y
  2. Nat Commun. 2024 May 31. 15(1): 4650
    The chromatin landscape of pathogenic transcriptional cell states in rheumatoid arthritis.
    Accelerating Medicines Partnership Program: Rheumatoid Arthritis and Systemic Lupus Erythematosus (AMP RA/SLE) Network
      Synovial tissue inflammation is a hallmark of rheumatoid arthritis (RA). Recent work has identified prominent pathogenic cell states in inflamed RA synovial tissue, such as T peripheral helper cells; however, the epigenetic regulation of these states has yet to be defined. Here, we examine genome-wide open chromatin at single-cell resolution in 30 synovial tissue samples, including 12 samples with transcriptional data in multimodal experiments. We identify 24 chromatin classes and predict their associated transcription factors, including a CD8 + GZMK+ class associated with EOMES and a lining fibroblast class associated with AP-1. By integrating with an RA tissue transcriptional atlas, we propose that these chromatin classes represent 'superstates' corresponding to multiple transcriptional cell states. Finally, we demonstrate the utility of this RA tissue chromatin atlas through the associations between disease phenotypes and chromatin class abundance, as well as the nomination of classes mediating the effects of putatively causal RA genetic variants.
    DOI:  https://doi.org/10.1038/s41467-024-48620-7
  3. Nat Immunol. 2024 May 29.
    Glucose restriction in antiviral defence.
    Emily L Goldberg.
      
    DOI:  https://doi.org/10.1038/s41590-024-01849-2
  4. Nat Commun. 2024 May 28. 15(1): 4285
    Long-read sequencing for 29 immune cell subsets reveals disease-linked isoforms.
    Jun Inamo, Akari Suzuki, Mahoko Takahashi Ueda, Kensuke Yamaguchi, Hiroshi Nishida, Katsuya Suzuki, Yuko Kaneko, Tsutomu Takeuchi, Hiroaki Hatano, Kazuyoshi Ishigaki, Yasushi Ishihama, Kazuhiko Yamamoto, Yuta Kochi.
      Alternative splicing events are a major causal mechanism for complex traits, but they have been understudied due to the limitation of short-read sequencing. Here, we generate a full-length isoform annotation of human immune cells from an individual by long-read sequencing for 29 cell subsets. This contains a number of unannotated transcripts and isoforms such as a read-through transcript of TOMM40-APOE in the Alzheimer's disease locus. We profile characteristics of isoforms and show that repetitive elements significantly explain the diversity of unannotated isoforms, providing insight into the human genome evolution. In addition, some of the isoforms are expressed in a cell-type specific manner, whose alternative 3'-UTRs usage contributes to their specificity. Further, we identify disease-associated isoforms by isoform switch analysis and by integration of several quantitative trait loci analyses with genome-wide association study data. Our findings will promote the elucidation of the mechanism of complex diseases via alternative splicing.
    DOI:  https://doi.org/10.1038/s41467-024-48615-4
  5. Nature. 2024 May 29.
    It's time for your performance review.
    Jane Brown.
      
    Keywords:  Arts; Culture
    DOI:  https://doi.org/10.1038/d41586-024-01527-1
  6. Nature. 2024 May 29.
    'Smart' antibiotic can kill deadly bacteria while sparing the microbiome.
    Fred Schwaller.
      
    Keywords:  Antibiotics; Drug discovery; Medical research; Microbiology
    DOI:  https://doi.org/10.1038/d41586-024-01566-8
  7. Nature. 2024 May 30.
    How I overcame my stage fright in the lab.
    Kwabena Asare.
      
    Keywords:  Careers; Conferences and meetings; Lab life
    DOI:  https://doi.org/10.1038/d41586-024-01616-1
  8. Nat Genet. 2024 May 29.
    Systematic decoding of cis gene regulation defines context-dependent control of the multi-gene costimulatory receptor locus in human T cells.
    Cody T Mowery, Jacob W Freimer, Zeyu Chen, Salvador Casaní-Galdón, Jennifer M Umhoefer, Maya M Arce, Ketrin Gjoni, Bence Daniel, Katalin Sandor, Benjamin G Gowen, Vinh Nguyen, Dimitre R Simeonov, Christian M Garrido, Gemma L Curie, Ralf Schmidt, Zachary Steinhart, Ansuman T Satpathy, Katherine S Pollard, Jacob E Corn, Bradley E Bernstein, Chun Jimmie Ye, Alexander Marson.
      Cis-regulatory elements (CREs) interact with trans regulators to orchestrate gene expression, but how transcriptional regulation is coordinated in multi-gene loci has not been experimentally defined. We sought to characterize the CREs controlling dynamic expression of the adjacent costimulatory genes CD28, CTLA4 and ICOS, encoding regulators of T cell-mediated immunity. Tiling CRISPR interference (CRISPRi) screens in primary human T cells, both conventional and regulatory subsets, uncovered gene-, cell subset- and stimulation-specific CREs. Integration with CRISPR knockout screens and assay for transposase-accessible chromatin with sequencing (ATAC-seq) profiling identified trans regulators influencing chromatin states at specific CRISPRi-responsive elements to control costimulatory gene expression. We then discovered a critical CCCTC-binding factor (CTCF) boundary that reinforces CRE interaction with CTLA4 while also preventing promiscuous activation of CD28. By systematically mapping CREs and associated trans regulators directly in primary human T cell subsets, this work overcomes longstanding experimental limitations to decode context-dependent gene regulatory programs in a complex, multi-gene locus critical to immune homeostasis.
    DOI:  https://doi.org/10.1038/s41588-024-01743-5
  9. Science. 2024 May 31. 384(6699): 961-962
    Germline variants alter immune surveillance.
    Nicola Waddell, Venkateswar Addala.
      Germline-derived epitopes shape tumor development through immunoediting.
    DOI:  https://doi.org/10.1126/science.adp7370
  10. Nat Immunol. 2024 May 30.
    Germline-targeting immunogens guide bnAb development.
    Tobias V Lanz.
      
    DOI:  https://doi.org/10.1038/s41590-024-01852-7
  11. Nat Commun. 2024 May 29. 15(1): 4564
    Development of a novel non-invasive biomarker panel for hepatic fibrosis in MASLD.
    Lars Verschuren, Anne Linde Mak, Arianne van Koppen, Serdar Özsezen, Sonia Difrancesco, Martien P M Caspers, Jessica Snabel, David van der Meer, Anne-Marieke van Dijk, Elias Badal Rashu, Puria Nabilou, Mikkel Parsberg Werge, Koen van Son, Robert Kleemann, Amanda J Kiliaan, Eric J Hazebroek, André Boonstra, Willem P Brouwer, Michail Doukas, Saurabh Gupta, Cornelis Kluft, Max Nieuwdorp, Joanne Verheij, Lise Lotte Gluud, Adriaan G Holleboom, Maarten E Tushuizen, Roeland Hanemaaijer.
      Accurate non-invasive biomarkers to diagnose metabolic dysfunction-associated steatotic liver disease (MASLD)-related fibrosis are urgently needed. This study applies a translational approach to develop a blood-based biomarker panel for fibrosis detection in MASLD. A molecular gene expression signature identified from a diet-induced MASLD mouse model (LDLr-/-.Leiden) is translated into human blood-based biomarkers based on liver biopsy transcriptomic profiles and protein levels in MASLD patient serum samples. The resulting biomarker panel consists of IGFBP7, SSc5D and Sema4D. LightGBM modeling using this panel demonstrates high accuracy in predicting MASLD fibrosis stage (F0/F1: AUC = 0.82; F2: AUC = 0.89; F3/F4: AUC = 0.87), which is replicated in an independent validation cohort. The overall accuracy of the model outperforms predictions by the existing markers Fib-4, APRI and FibroScan. In conclusion, here we show a disease mechanism-related blood-based biomarker panel with three biomarkers which is able to identify MASLD patients with mild or advanced hepatic fibrosis with high accuracy.
    DOI:  https://doi.org/10.1038/s41467-024-48956-0
  12. Nat Commun. 2024 May 29. 15(1): 4527
    Pancreatic beta-cell IL-22 receptor deficiency induces age-dependent dysregulation of insulin biosynthesis and systemic glucose homeostasis.
    Haressh Sajiir, Kuan Yau Wong, Alexandra Müller, Sahar Keshvari, Lucy Burr, Elena Aiello, Teresa Mezza, Andrea Giaccari, Guido Sebastiani, Francesco Dotta, Grant A Ramm, Graeme A Macdonald, Michael A McGuckin, Johannes B Prins, Sumaira Z Hasnain.
      The IL-22RA1 receptor is highly expressed in the pancreas, and exogenous IL-22 has been shown to reduce endoplasmic reticulum and oxidative stress in human pancreatic islets and promote secretion of high-quality insulin from beta-cells. However, the endogenous role of IL-22RA1 signaling on these cells remains unclear. Here, we show that antibody neutralisation of IL-22RA1 in cultured human islets leads to impaired insulin quality and increased cellular stress. Through the generation of mice lacking IL-22ra1 specifically on pancreatic alpha- or beta-cells, we demonstrate that ablation of murine beta-cell IL-22ra1 leads to similar decreases in insulin secretion, quality and islet regeneration, whilst increasing islet cellular stress, inflammation and MHC II expression. These changes in insulin secretion led to impaired glucose tolerance, a finding more pronounced in female animals compared to males. Our findings attribute a regulatory role for endogenous pancreatic beta-cell IL-22ra1 in insulin secretion, islet regeneration, inflammation/cellular stress and appropriate systemic metabolic regulation.
    DOI:  https://doi.org/10.1038/s41467-024-48320-2
  13. Science. 2024 May 31. 384(6699): 962-963
    Living bioelectronics resolve inflammation.
    Peder S Olofsson.
      Coupling skin bacteria and electronics opens paths to adaptive treatment of inflammation.
    DOI:  https://doi.org/10.1126/science.adp5201
  14. Nat Commun. 2024 May 28. 15(1): 4425
    Alternative protein sources: science powered startups to fuel food innovation.
    Elena Lurie-Luke.
      Harnessing the potential of considerable food security efforts requires the ability to translate them into commercial applications. This is particularly true for alternative protein sources and startups being on the forefront of innovation represent the latest advancements in this field.
    DOI:  https://doi.org/10.1038/s41467-024-47091-0
  15. Nat Immunol. 2024 May 29.
    Cytokine polarized, alternatively activated bone marrow neutrophils drive axon regeneration.
    Andrew D Jerome, Andrew R Sas, Yan Wang, Luke A Hammond, Jing Wen, Jeffrey R Atkinson, Amy Webb, Tom Liu, Benjamin M Segal.
      The adult central nervous system (CNS) possesses a limited capacity for self-repair. Severed CNS axons typically fail to regrow. There is an unmet need for treatments designed to enhance neuronal viability, facilitate axon regeneration and ultimately restore lost neurological functions to individuals affected by traumatic CNS injury, multiple sclerosis, stroke and other neurological disorders. Here we demonstrate that both mouse and human bone marrow neutrophils, when polarized with a combination of recombinant interleukin-4 (IL-4) and granulocyte colony-stimulating factor (G-CSF), upregulate alternative activation markers and produce an array of growth factors, thereby gaining the capacity to promote neurite outgrowth. Moreover, adoptive transfer of IL-4/G-CSF-polarized bone marrow neutrophils into experimental models of CNS injury triggered substantial axon regeneration within the optic nerve and spinal cord. These findings have far-reaching implications for the future development of autologous myeloid cell-based therapies that may bring us closer to effective solutions for reversing CNS damage.
    DOI:  https://doi.org/10.1038/s41590-024-01836-7
  16. Nat Metab. 2024 May;6(5): 847-860
    Hippo-YAP/TAZ signalling coordinates adipose plasticity and energy balance by uncoupling leptin expression from fat mass.
    Sungwoo Choi, Ju-Gyeong Kang, Yen T H Tran, Sun-Hye Jeong, Kun-Young Park, Hyemi Shin, Young Hoon Kim, Myungsun Park, Hahn Nahmgoong, Taejun Seol, Haeyon Jeon, Yeongmin Kim, Sanghee Park, Hee-Joo Kim, Min-Seob Kim, Xiaoxu Li, Maroun Bou Sleiman, Eries Lee, Jinhyuk Choi, David Eisenbarth, Sang Heon Lee, Suhyeon Cho, David D Moore, Johan Auwerx, Il-Young Kim, Jae Bum Kim, Jong-Eun Park, Dae-Sik Lim, Jae Myoung Suh.
      Adipose tissues serve as an energy reservoir and endocrine organ, yet the mechanisms that coordinate these functions remain elusive. Here, we show that the transcriptional coregulators, YAP and TAZ, uncouple fat mass from leptin levels and regulate adipocyte plasticity to maintain metabolic homeostasis. Activating YAP/TAZ signalling in adipocytes by deletion of the upstream regulators Lats1 and Lats2 results in a profound reduction in fat mass by converting mature adipocytes into delipidated progenitor-like cells, but does not cause lipodystrophy-related metabolic dysfunction, due to a paradoxical increase in circulating leptin levels. Mechanistically, we demonstrate that YAP/TAZ-TEAD signalling upregulates leptin expression by directly binding to an upstream enhancer site of the leptin gene. We further show that YAP/TAZ activity is associated with, and functionally required for, leptin regulation during fasting and refeeding. These results suggest that adipocyte Hippo-YAP/TAZ signalling constitutes a nexus for coordinating adipose tissue lipid storage capacity and systemic energy balance through the regulation of adipocyte plasticity and leptin gene transcription.
    DOI:  https://doi.org/10.1038/s42255-024-01045-4
  17. Nat Commun. 2024 May 25. 15(1): 4469
    Rab30 facilitates lipid homeostasis during fasting.
    Danielle M Smith, Brian Y Liu, Michael J Wolfgang.
      To facilitate inter-tissue communication and the exchange of proteins, lipoproteins, and metabolites with the circulation, hepatocytes have an intricate and efficient intracellular trafficking system regulated by small Rab GTPases. Here, we show that Rab30 is induced in the mouse liver by fasting, which is amplified in liver-specific carnitine palmitoyltransferase 2 knockout mice (Cpt2L-/-) lacking the ability to oxidize fatty acids, in a Pparα-dependent manner. Live-cell super-resolution imaging and in vivo proximity labeling demonstrates that Rab30-marked vesicles are highly dynamic and interact with proteins throughout the secretory pathway. Rab30 whole-body, liver-specific, and Rab30; Cpt2 liver-specific double knockout (DKO) mice are viable with intact Golgi ultrastructure, although Rab30 deficiency in DKO mice suppresses the serum dyslipidemia observed in Cpt2L-/- mice. Corresponding with decreased serum triglyceride and cholesterol levels, DKO mice exhibit decreased circulating but not hepatic ApoA4 protein, indicative of a trafficking defect. Together, these data suggest a role for Rab30 in the selective sorting of lipoproteins to influence hepatocyte and circulating triglyceride levels, particularly during times of excessive lipid burden.
    DOI:  https://doi.org/10.1038/s41467-024-48959-x
  18. Nat Commun. 2024 May 25. 15(1): 4462
    Metabolism of L-arabinose converges with virulence regulation to promote enteric pathogen fitness.
    Curtis Cottam, Rhys T White, Lauren C Beck, Christopher J Stewart, Scott A Beatson, Elisabeth C Lowe, Rhys Grinter, James P R Connolly.
      Virulence and metabolism are often interlinked to control the expression of essential colonisation factors in response to host-associated signals. Here, we identified an uncharacterised transporter of the dietary monosaccharide ʟ-arabinose that is widely encoded by the zoonotic pathogen enterohaemorrhagic Escherichia coli (EHEC), required for full competitive fitness in the mouse gut and highly expressed during human infection. Discovery of this transporter suggested that EHEC strains have an enhanced ability to scavenge ʟ-arabinose and therefore prompted us to investigate the impact of this nutrient on pathogenesis. Accordingly, we discovered that ʟ-arabinose enhances expression of the EHEC type 3 secretion system, increasing its ability to colonise host cells, and that the underlying mechanism is dependent on products of its catabolism rather than the sensing of ʟ-arabinose as a signal. Furthermore, using the murine pathogen Citrobacter rodentium, we show that ʟ-arabinose metabolism provides a fitness benefit during infection via virulence factor regulation, as opposed to supporting pathogen growth. Finally, we show that this mechanism is not restricted to ʟ-arabinose and extends to other pentose sugars with a similar metabolic fate. This work highlights the importance integrating central metabolism with virulence regulation in order to maximise competitive fitness of enteric pathogens within the host-niche.
    DOI:  https://doi.org/10.1038/s41467-024-48933-7
  19. Nat Neurosci. 2024 May 27.
    NG2 glia protect against prion neurotoxicity by inhibiting microglia-to-neuron prostaglandin E2 signaling.
    Yingjun Liu, Jingjing Guo, Maja Matoga, Marina Korotkova, Per-Johan Jakobsson, Adriano Aguzzi.
      Oligodendrocyte-lineage cells, including NG2 glia, undergo prominent changes in various neurodegenerative disorders. Here, we identify a neuroprotective role for NG2 glia against prion toxicity. NG2 glia were activated after prion infection in cerebellar organotypic cultured slices (COCS) and in brains of prion-inoculated mice. In both model systems, depletion of NG2 glia exacerbated prion-induced neurodegeneration and accelerated prion pathology. Loss of NG2 glia enhanced the biosynthesis of prostaglandin E2 (PGE2) by microglia, which augmented prion neurotoxicity through binding to the EP4 receptor. Pharmacological or genetic inhibition of PGE2 biosynthesis attenuated prion-induced neurodegeneration in COCS and mice, reduced the enhanced neurodegeneration in NG2-glia-depleted COCS after prion infection, and dampened the acceleration of prion disease in NG2-glia-depleted mice. These data unveil a non-cell-autonomous interaction between NG2 glia and microglia in prion disease and suggest that PGE2 signaling may represent an actionable target against prion diseases.
    DOI:  https://doi.org/10.1038/s41593-024-01663-x
  20. Nature. 2024 May;629(8014): S4-S6
    Natural killer cells show their cancer-fighting worth.
    Amanda B Keener.
      
    Keywords:  Cancer; Drug discovery; Immunology; Therapeutics
    DOI:  https://doi.org/10.1038/d41586-024-01427-4
  21. Nat Commun. 2024 May 31. 15(1): 4646
    AgRP neuron cis-regulatory analysis across hunger states reveals that IRF3 mediates leptin's acute effects.
    Frankie D Heyward, Nan Liu, Christopher Jacobs, Natalia L S Machado, Rachael Ivison, Aykut Uner, Harini Srinivasan, Suraj J Patel, Anton Gulko, Tyler Sermersheim, Linus Tsai, Evan D Rosen.
      AgRP neurons in the arcuate nucleus of the hypothalamus (ARC) coordinate homeostatic changes in appetite associated with fluctuations in food availability and leptin signaling. Identifying the relevant transcriptional regulatory pathways in these neurons has been a priority, yet such attempts have been stymied due to their low abundance and the rich cellular diversity of the ARC. Here we generated AgRP neuron-specific transcriptomic and chromatin accessibility profiles from male mice during three distinct hunger states of satiety, fasting-induced hunger, and leptin-induced hunger suppression. Cis-regulatory analysis of these integrated datasets enabled the identification of 18 putative hunger-promoting and 29 putative hunger-suppressing transcriptional regulators in AgRP neurons, 16 of which were predicted to be transcriptional effectors of leptin. Within our dataset, Interferon regulatory factor 3 (IRF3) emerged as a leading candidate mediator of leptin-induced hunger-suppression. Measures of IRF3 activation in vitro and in vivo reveal an increase in IRF3 nuclear occupancy following leptin administration. Finally, gain- and loss-of-function experiments in vivo confirm the role of IRF3 in mediating the acute satiety-evoking effects of leptin in AgRP neurons. Thus, our findings identify IRF3 as a key mediator of the acute hunger-suppressing effects of leptin in AgRP neurons.
    DOI:  https://doi.org/10.1038/s41467-024-48885-y
  22. Nat Cell Biol. 2024 May 31.
    Unfolding emergency calls stress granules to the ER.
    David Pincus, Scott A Oakes.
      
    DOI:  https://doi.org/10.1038/s41556-024-01434-7
  23. Nat Commun. 2024 May 30. 15(1): 4605
    Inflammation causes insulin resistance in mice via interferon regulatory factor 3 (IRF3)-mediated reduction in FAHFA levels.
    Shuai Yan, Anna Santoro, Micah J Niphakis, Antonio M Pinto, Christopher L Jacobs, Rasheed Ahmad, Radu M Suciu, Bryan R Fonslow, Rachel A Herbst-Graham, Nhi Ngo, Cassandra L Henry, Dylan M Herbst, Alan Saghatelian, Barbara B Kahn, Evan D Rosen.
      Obesity-induced inflammation causes metabolic dysfunction, but the mechanisms remain elusive. Here we show that the innate immune transcription factor interferon regulatory factor (IRF3) adversely affects glucose homeostasis through induction of the endogenous FAHFA hydrolase androgen induced gene 1 (AIG1) in adipocytes. Adipocyte-specific knockout of IRF3 protects male mice against high-fat diet-induced insulin resistance, whereas overexpression of IRF3 or AIG1 in adipocytes promotes insulin resistance on a high-fat diet. Furthermore, pharmacological inhibition of AIG1 reversed obesity-induced insulin resistance and restored glucose homeostasis in the setting of adipocyte IRF3 overexpression. We, therefore, identify the adipocyte IRF3/AIG1 axis as a crucial link between obesity-induced inflammation and insulin resistance and suggest an approach for limiting the metabolic dysfunction accompanying obesity.
    DOI:  https://doi.org/10.1038/s41467-024-48220-5
  24. Nature. 2024 May 28.
    Autistic people three times more likely to develop Parkinson's-like symptoms.
    Miryam Naddaf.
      
    Keywords:  Autism spectrum disorders; Parkinson's disease
    DOI:  https://doi.org/10.1038/d41586-024-01572-w
  25. Cell Rep. 2024 May 30. pii: S2211-1247(24)00587-4. [Epub ahead of print]43(6): 114259
    A targeted single mutation in influenza A virus universal epitope transforms immunogenicity and protective immunity via CD4+ T cell activation.
    Sarah Hulin-Curtis, James K Geary, Bruce J MacLachlan, Danny M Altmann, Laury Baillon, David K Cole, Alex Greenshields-Watson, Sophie J Hesketh, Ian R Humphreys, Ian M Jones, Sarah N Lauder, Georgina H Mason, Kathryn Smart, D Oliver Scourfield, Jake Scott, Ksenia Sukhova, Richard J Stanton, Aaron Wall, Pierre J Rizkallah, Wendy S Barclay, Awen Gallimore, Andrew Godkin.
      CD4+ T cells are central to adaptive immunity. Their role in cross-protection in viral infections such as influenza and severe acute respiratory syndrome (SARS) is well documented; however, molecular rules governing T cell receptor (TCR) engagement of peptide-human leukocyte antigen (pHLA) class II are less understood. Here, we exploit an aspect of HLA class II presentation, the peptide-flanking residues (PFRs), to "tune" CD4+ T cell responses within an in vivo model system of influenza. Using a recombinant virus containing targeted substitutions at immunodominant HLA-DR1 epitopes, we demonstrate limited weight loss and improved clinical scores after heterosubtypic re-challenge. We observe enhanced protection linked to lung-derived influenza-specific CD4+ and CD8+ T cells prior to re-infection. Structural analysis of the ternary TCR:pHLA complex identifies that flanking amino acids influence side chains in the core 9-mer peptide, increasing TCR affinity. Augmentation of CD4+ T cell immunity is achievable with a single mutation, representing a strategy to enhance adaptive immunity that is decoupled from vaccine modality.
    Keywords:  CD4(+) T cell; CP: Immunology; HLA-DR1; influenza A virus; lung CD8(+) tissue-resident memory T cell; peptide-flanking residues; vaccine
    DOI:  https://doi.org/10.1016/j.celrep.2024.114259
  26. Cell Death Dis. 2024 May 29. 15(5): 371
    A snapshot into the transcriptomic landscape of apoptosis and ferroptosis in cancer.
    Yaron Vinik, Sima Lev.
      
    DOI:  https://doi.org/10.1038/s41419-024-06766-8
  27. Nat Biotechnol. 2024 May 28.
    Enhancing prime editing in hematopoietic stem and progenitor cells by modulating nucleotide metabolism.
    Sébastien Levesque, Andrea Cosentino, Archana Verma, Pietro Genovese, Daniel E Bauer.
      Therapeutic prime editing of hematopoietic stem and progenitor cells (HSPCs) holds great potential to remedy blood disorders. Quiescent cells have low nucleotide levels and resist retroviral infection, and it is possible that nucleotide metabolism could limit reverse transcription-mediated prime editing in HSPCs. We demonstrate that deoxynucleoside supplementation and Vpx-mediated degradation of SAMHD1 improve prime editing efficiency in HSPCs, especially when coupled with editing approaches that evade mismatch repair.
    DOI:  https://doi.org/10.1038/s41587-024-02266-4
  28. Nat Genet. 2024 May 28.
    Novel somatic mutations in blood driving age-related clonal hematopoiesis.
      
    DOI:  https://doi.org/10.1038/s41588-024-01756-0
  29. Sci Adv. 2024 May 31. 10(22): eadn2050
    CLUH maintains functional mitochondria and translation in motoneuronal axons and prevents peripheral neuropathy.
    Marta Zaninello, Tim Schlegel, Hendrik Nolte, Mujeeb Pirzada, Elisa Savino, Esther Barth, Ines Klein, Hauke Wüstenberg, Tesmin Uddin, Lisa Wolff, Brunhilde Wirth, Helmar C Lehmann, Jean-Michel Cioni, Thomas Langer, Elena I Rugarli.
      Transporting and translating mRNAs in axons is crucial for neuronal viability. Local synthesis of nuclear-encoded mitochondrial proteins protects long-lived axonal mitochondria from damage; however, the regulatory factors involved are largely unknown. We show that CLUH, which binds mRNAs encoding mitochondrial proteins, prevents peripheral neuropathy and motor deficits in the mouse. CLUH is enriched in the growth cone of developing spinal motoneurons and is required for their growth. The lack of CLUH affects the abundance of target mRNAs and the corresponding mitochondrial proteins more prominently in axons, leading to ATP deficits in the growth cone. CLUH interacts with ribosomal subunits, translation initiation, and ribosome recycling components and preserves axonal translation. Overexpression of the ribosome recycling factor ABCE1 rescues the mRNA and translation defects, as well as the growth cone size, in CLUH-deficient motoneurons. Thus, we demonstrate a role for CLUH in mitochondrial quality control and translational regulation in axons, which is essential for their development and long-term integrity and function.
    DOI:  https://doi.org/10.1126/sciadv.adn2050
  30. Nature. 2024 May;629(8014): 1200
    I study artefacts left in prehistoric caves.
    James Mitchell Crow.
      
    Keywords:  Archaeology; Careers; History
    DOI:  https://doi.org/10.1038/d41586-024-01526-2
  31. Nat Rev Immunol. 2024 May 31.
    Stiff tumours exhaust T cells.
    Lucy Bird.
      
    DOI:  https://doi.org/10.1038/s41577-024-01053-1
  32. Sci Adv. 2024 May 31. 10(22): eadj1431
    13C metabolite tracing reveals glutamine and acetate as critical in vivo fuels for CD8 T cells.
    Eric H Ma, Michael S Dahabieh, Lisa M DeCamp, Irem Kaymak, Susan M Kitchen-Goosen, Brandon M Oswald, Joseph Longo, Dominic G Roy, Mark J Verway, Radia M Johnson, Bozena Samborska, Lauren R Duimstra, Catherine A Scullion, Mya Steadman, Matthew Vos, Thomas P Roddy, Connie M Krawczyk, Kelsey S Williams, Ryan D Sheldon, Russell G Jones.
      Infusion of 13C-labeled metabolites provides a gold standard for understanding the metabolic processes used by T cells during immune responses in vivo. Through infusion of 13C-labeled metabolites (glucose, glutamine, and acetate) in Listeria monocytogenes-infected mice, we demonstrate that CD8 T effector (Teff) cells use metabolites for specific pathways during specific phases of activation. Highly proliferative early Teff cells in vivo shunt glucose primarily toward nucleotide synthesis and leverage glutamine anaplerosis in the tricarboxylic acid (TCA) cycle to support adenosine triphosphate and de novo pyrimidine synthesis. In addition, early Teff cells rely on glutamic-oxaloacetic transaminase 1 (Got1)-which regulates de novo aspartate synthesis-for effector cell expansion in vivo. CD8 Teff cells change fuel preference over the course of infection, switching from glutamine- to acetate-dependent TCA cycle metabolism late in infection. This study provides insights into the dynamics of Teff metabolism, illuminating distinct pathways of fuel consumption associated with CD8 Teff cell function in vivo.
    DOI:  https://doi.org/10.1126/sciadv.adj1431
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