bims-nimamd Biomed News
on Neuroimmunity and neuroinflammation in ageing and metabolic disease
Issue of 2022‒09‒25
forty-six papers selected by
Fawaz Alzaïd
Sorbonne Université
  1. tRNA-m1A modification promotes T cell expansion via efficient MYC protein synthesis.
  2. CNS myelination requires VAMP2/3-mediated membrane expansion in oligodendrocytes.
  3. A Stk4-Foxp3-NF-κB p65 transcriptional complex promotes Treg cell activation and homeostasis.
  4. The immune landscape of human thymic epithelial tumors.
  5. How do humans resist tuberculosis? With a metabolic protein's help.
  6. An anti-inflammatory activation sequence governs macrophage transcriptional dynamics during tissue injury in zebrafish.
  7. Three-dimensional genome organization in immune cell fate and function.
  8. Mesenchymal and adrenergic cell lineage states in neuroblastoma possess distinct immunogenic phenotypes.
  9. Intrinsic bias estimation for improved analysis of bulk and single-cell chromatin accessibility profiles using SELMA.
  10. Activation of the insulin receptor by an insulin mimetic peptide.
  11. Cytoplasmic organization promotes protein diffusion in Xenopus extracts.
  12. Learning enhances encoding of time and temporal surprise in mouse primary sensory cortex.
  13. Intracellular energy controls dynamics of stress-induced ribonucleoprotein granules.
  14. Single-cell transcriptomics reveal cellular diversity of aortic valve and the immunomodulation by PPARγ during hyperlipidemia.
  15. Cell region fingerprints enable highly precise single-cell tracking and lineage reconstruction.
  16. Revisiting life history and morphological proxies for early mammaliaform metabolic rates.
  17. Cellular and transcriptional dynamics of human neutrophils at steady state and upon stress.
  18. The evolutionary dynamics of extrachromosomal DNA in human cancers.
  19. Differential dysregulation of granule subsets in WASH-deficient neutrophil leukocytes resulting in inflammation.
  20. miR204 potentially promotes non-alcoholic fatty liver disease by inhibition of cpt1a in mouse hepatocytes.
  21. Reduced endosomal microautophagy activity in aging associates with enhanced exocyst-mediated protein secretion.
  22. m1A tRNA modification facilitates rapid T cell proliferation.
  23. APRIL Drives a Coordinated but Diverse Response as a Foundation for Plasma Cell Longevity.
  24. Diabetes downregulates the antimicrobial peptide psoriasin and increases E. coli burden in the urinary bladder.
  25. Apolipoprotein E mediates cell resistance to influenza virus infection.
  26. CTLs Get SMAD When Pathogens Tell Them Where to Go.
  27. NUDT21 limits CD19 levels through alternative mRNA polyadenylation in B cell acute lymphoblastic leukemia.
  28. Bacterial diet modulates tamoxifen-induced death via host fatty acid metabolism.
  29. Ubiquitination of CLIP-170 family protein restrains polarized growth upon DNA replication stress.
  30. A cellular hierarchy in melanoma uncouples growth and metastasis.
  31. Long-primed germinal centres with enduring affinity maturation and clonal migration.
  32. Single-cell profiling identifies mechanisms of inflammatory heterogeneity in chronic rhinosinusitis.
  33. Flow pattern-dependent mitochondrial dynamics regulates the metabolic profile and inflammatory state of endothelial cells.
  34. Chromatin organizer SATB1 controls the cell identity of CD4+ CD8+ double-positive thymocytes by regulating the activity of super-enhancers.
  35. Blockade of TGF-β signaling reactivates HIV-1/SIV reservoirs and immune responses in vivo.
  36. High-fructose feeding suppresses cold-stimulated brown adipose tissue glucose uptake independently of changes in thermogenesis and the gut microbiome.
  37. Hepatology highlights.
  38. Multi-omic brain and behavioral correlates of cell-free fetal DNA methylation in macaque maternal obesity models.
  39. Live imaging and conditional disruption of native PCP activity using endogenously tagged zebrafish sfGFP-Vangl2.
  40. The adipocyte-enriched secretory protein tetranectin exacerbates type 2 diabetes by inhibiting insulin secretion from β cells.
  41. PD-1/PD-L1 blockade abrogates a dysfunctional innate-adaptive immune axis in critical β-coronavirus disease.
  42. Mechanistic understanding of human SLFN11.
  43. Transition metal dichalcogenide metaphotonic and self-coupled polaritonic platform grown by chemical vapor deposition.
  44. Ca2+ -independent transmission at the central synapse formed between dorsal root ganglion and dorsal horn neurons.
  45. Characterization of cellular senescence in aging skeletal muscle.
  46. Impaired immune response drives age-dependent severity of COVID-19.
  1. Nat Immunol. 2022 Sep 22.
    tRNA-m1A modification promotes T cell expansion via efficient MYC protein synthesis.
    Yongbo Liu, Jing Zhou, Xiaoyu Li, Xiaoting Zhang, Jintong Shi, Xuefei Wang, Hao Li, Shan Miao, Huifang Chen, Xiaoxiao He, Liting Dong, Gap Ryol Lee, Junke Zheng, Ru-Juan Liu, Bing Su, Youqiong Ye, Richard A Flavell, Chengqi Yi, Yuzhang Wu, Hua-Bing Li.
      Naive T cells undergo radical changes during the transition from dormant to hyperactive states upon activation, which necessitates de novo protein production via transcription and translation. However, the mechanism whereby T cells globally promote translation remains largely unknown. Here, we show that on exit from quiescence, T cells upregulate transfer RNA (tRNA) m1A58 'writer' proteins TRMT61A and TRMT6, which confer m1A58 RNA modification on a specific subset of early expressed tRNAs. These m1A-modified early tRNAs enhance translation efficiency, enabling rapid and necessary synthesis of MYC and of a specific group of key functional proteins. The MYC protein then guides the exit of naive T cells from a quiescent state into a proliferative state and promotes rapid T cell expansion after activation. Conditional deletion of the Trmt61a gene in mouse CD4+ T cells causes MYC protein deficiency and cell cycle arrest, disrupts T cell expansion upon cognate antigen stimulation and alleviates colitis in a mouse adoptive transfer colitis model. Our study elucidates for the first time, to our knowledge, the in vivo physiological roles of tRNA-m1A58 modification in T cell-mediated pathogenesis and reveals a new mechanism of tRNA-m1A58-controlled T cell homeostasis and signal-dependent translational control of specific key proteins.
    DOI:  https://doi.org/10.1038/s41590-022-01301-3
  2. Nat Commun. 2022 Sep 23. 13(1): 5583
    CNS myelination requires VAMP2/3-mediated membrane expansion in oligodendrocytes.
    Mable Lam, Koji Takeo, Rafael G Almeida, Madeline H Cooper, Kathryn Wu, Manasi Iyer, Husniye Kantarci, J Bradley Zuchero.
      Myelin is required for rapid nerve signaling and is emerging as a key driver of CNS plasticity and disease. How myelin is built and remodeled remains a fundamental question of neurobiology. Central to myelination is the ability of oligodendrocytes to add vast amounts of new cell membrane, expanding their surface areas by many thousand-fold. However, how oligodendrocytes add new membrane to build or remodel myelin is not fully understood. Here, we show that CNS myelin membrane addition requires exocytosis mediated by the vesicular SNARE proteins VAMP2/3. Genetic inactivation of VAMP2/3 in myelinating oligodendrocytes caused severe hypomyelination and premature death without overt loss of oligodendrocytes. Through live imaging, we discovered that VAMP2/3-mediated exocytosis drives membrane expansion within myelin sheaths to initiate wrapping and power sheath elongation. In conjunction with membrane expansion, mass spectrometry of oligodendrocyte surface proteins revealed that VAMP2/3 incorporates axon-myelin adhesion proteins that are collectively required to form nodes of Ranvier. Together, our results demonstrate that VAMP2/3-mediated membrane expansion in oligodendrocytes is indispensable for myelin formation, uncovering a cellular pathway that could sculpt myelination patterns in response to activity-dependent signals or be therapeutically targeted to promote regeneration in disease.
    DOI:  https://doi.org/10.1038/s41467-022-33200-4
  3. Sci Immunol. 2022 Sep 23. 7(75): eabl8357
    A Stk4-Foxp3-NF-κB p65 transcriptional complex promotes Treg cell activation and homeostasis.
    Ye Cui, Mehdi Benamar, Klaus Schmitz-Abe, Varsha Poondi-Krishnan, Qian Chen, Bat-Erdene Jugder, Benoit Fatou, Jason Fong, Yuelin Zhong, Stuti Mehta, Altantsetseg Buyanbat, Beray Selver Eklioglu, Esra Karabiber, Safa Baris, Ayca Kiykim, Sevgi Keles, Emmanuel Stephen-Victor, Claudia Angelini, Louis-Marie Charbonnier, Talal A Chatila.
      The molecular programs involved in regulatory T (Treg) cell activation and homeostasis remain incompletely understood. Here, we show that T cell receptor (TCR) signaling in Treg cells induces the nuclear translocation of serine/threonine kinase 4 (Stk4), leading to the formation of an Stk4-NF-κB p65-Foxp3 complex that regulates Foxp3- and p65-dependent transcriptional programs. This complex was stabilized by Stk4-dependent phosphorylation of Foxp3 on serine-418. Stk4 deficiency in Treg cells, either alone or in combination with its homolog Stk3, precipitated a fatal autoimmune lymphoproliferative disease in mice characterized by decreased Treg cell p65 expression and nuclear translocation, impaired NF-κB p65-Foxp3 complex formation, and defective Treg cell activation. In an adoptive immunotherapy model, overexpression of p65 or the phosphomimetic Foxp3S418E in Stk3/4-deficient Treg cells ameliorated their immune regulatory defects. Our studies identify Stk4 as an essential TCR-responsive regulator of p65-Foxp3-dependent transcription that promotes Treg cell-mediated immune tolerance.
    DOI:  https://doi.org/10.1126/sciimmunol.abl8357
  4. Nat Commun. 2022 Sep 17. 13(1): 5463
    The immune landscape of human thymic epithelial tumors.
    Zhongwei Xin, Mingjie Lin, Zhixing Hao, Di Chen, Yongyuan Chen, Xiaoke Chen, Xia Xu, Jinfan Li, Dang Wu, Ying Chai, Pin Wu.
      Human thymic epithelial tumors (TET) are common malignancies in the anterior mediastinum with limited biological understanding. Here we show, by single cell analysis of the immune landscape, that the developmental pattern of intra-tumoral T-cells identify three types within TETs. We characterize the developmental alterations and TCR repertoires of tumor-infiltrating T cells in the context of the distinguishing epithelial tumor cell types. We demonstrate that a subset of tumor cells, featuring medullary thymic epithelial cell (TEC) phenotype and marked by KRT14/GNB3 expression, accumulate in type 1 TETs, while T-cell positive selection is inhibited. Type 2 TETs are dominated by CCL25+ cortical TEC-like cells that appear to promote T-cell positive selection. Interestingly, the CHI3L1+ medullary TEC-like cells that are the characteristic feature of type 3 TETs don't seem to support T-cell development, however, they may induce a tissue-resident CD8+ T cell response. In summary, our work suggests that the molecular subtype of epithelial tumour cells in TETs determine their tumour immune microenvironment, thus GNB3 and CHI3L1 might predict the immunological behavior and hence prognosis of these tumours.
    DOI:  https://doi.org/10.1038/s41467-022-33170-7
  5. Nature. 2022 Sep 23.
    How do humans resist tuberculosis? With a metabolic protein's help.
      
    Keywords:  Infection
    DOI:  https://doi.org/10.1038/d41586-022-02987-z
  6. Nat Commun. 2022 Sep 20. 13(1): 5356
    An anti-inflammatory activation sequence governs macrophage transcriptional dynamics during tissue injury in zebrafish.
    Nicolas Denans, Nhung T T Tran, Madeleine E Swall, Daniel C Diaz, Jillian Blanck, Tatjana Piotrowski.
      Macrophages are essential for tissue repair and regeneration. Yet, the molecular programs, as well as the timing of their activation during and after tissue injury are poorly defined. Using a high spatio-temporal resolution single cell analysis of macrophages coupled with live imaging after sensory hair cell death in zebrafish, we find that the same population of macrophages transitions through a sequence of three major anti-inflammatory activation states. Macrophages first show a signature of glucocorticoid activation, then IL-10 signaling and finally the induction of oxidative phosphorylation by IL-4/Polyamine signaling. Importantly, loss-of-function of glucocorticoid and IL-10 signaling shows that each step of the sequence is independently activated. Lastly, we show that IL-10 and IL-4 signaling act synergistically to promote synaptogenesis between hair cells and efferent neurons during regeneration. Our results show that macrophages, in addition to a switch from M1 to M2, sequentially and independently transition though three anti-inflammatory pathways in vivo during tissue injury in a regenerating organ.
    DOI:  https://doi.org/10.1038/s41467-022-33015-3
  7. Nat Rev Immunol. 2022 Sep 20.
    Three-dimensional genome organization in immune cell fate and function.
    Sergi Cuartero, Grégoire Stik, Ralph Stadhouders.
      Immune cell development and activation demand the precise and coordinated control of transcriptional programmes. Three-dimensional (3D) organization of the genome has emerged as an important regulator of chromatin state, transcriptional activity and cell identity by facilitating or impeding long-range genomic interactions among regulatory elements and genes. Chromatin folding thus enables cell type-specific and stimulus-specific transcriptional responses to extracellular signals, which are essential for the control of immune cell fate, for inflammatory responses and for generating a diverse repertoire of antigen receptor specificities. Here, we review recent findings connecting 3D genome organization to the control of immune cell differentiation and function, and discuss how alterations in genome folding may lead to immune dysfunction and malignancy.
    DOI:  https://doi.org/10.1038/s41577-022-00774-5
  8. Nat Cancer. 2022 Sep 22.
    Mesenchymal and adrenergic cell lineage states in neuroblastoma possess distinct immunogenic phenotypes.
    Satyaki Sengupta, Sanjukta Das, Angela C Crespo, Annelisa M Cornel, Anand G Patel, Navin R Mahadevan, Marco Campisi, Alaa K Ali, Bandana Sharma, Jared H Rowe, Hao Huang, David N Debruyne, Esther D Cerda, Malgorzata Krajewska, Ruben Dries, Minyue Chen, Shupei Zhang, Luigi Soriano, Malkiel A Cohen, Rogier Versteeg, Rudolf Jaenisch, Stefani Spranger, Rizwan Romee, Brian C Miller, David A Barbie, Stefan Nierkens, Michael A Dyer, Judy Lieberman, Rani E George.
      Apart from the anti-GD2 antibody, immunotherapy for neuroblastoma has had limited success due to immune evasion mechanisms, coupled with an incomplete understanding of predictors of response. Here, from bulk and single-cell transcriptomic analyses, we identify a subset of neuroblastomas enriched for transcripts associated with immune activation and inhibition and show that these are predominantly characterized by gene expression signatures of the mesenchymal lineage state. By contrast, tumors expressing adrenergic lineage signatures are less immunogenic. The inherent presence or induction of the mesenchymal state through transcriptional reprogramming or therapy resistance is accompanied by innate and adaptive immune gene activation through epigenetic remodeling. Mesenchymal lineage cells promote T cell infiltration by secreting inflammatory cytokines, are efficiently targeted by cytotoxic T and natural killer cells and respond to immune checkpoint blockade. Together, we demonstrate that distinct immunogenic phenotypes define the divergent lineage states of neuroblastoma and highlight the immunogenic potential of the mesenchymal lineage.
    DOI:  https://doi.org/10.1038/s43018-022-00427-5
  9. Nat Commun. 2022 Sep 21. 13(1): 5533
    Intrinsic bias estimation for improved analysis of bulk and single-cell chromatin accessibility profiles using SELMA.
    Shengen Shawn Hu, Lin Liu, Qi Li, Wenjing Ma, Michael J Guertin, Clifford A Meyer, Ke Deng, Tingting Zhang, Chongzhi Zang.
      Genome-wide profiling of chromatin accessibility by DNase-seq or ATAC-seq has been widely used to identify regulatory DNA elements and transcription factor binding sites. However, enzymatic DNA cleavage exhibits intrinsic sequence biases that confound chromatin accessibility profiling data analysis. Existing computational tools are limited in their ability to account for such intrinsic biases and not designed for analyzing single-cell data. Here, we present Simplex Encoded Linear Model for Accessible Chromatin (SELMA), a computational method for systematic estimation of intrinsic cleavage biases from genomic chromatin accessibility profiling data. We demonstrate that SELMA yields accurate and robust bias estimation from both bulk and single-cell DNase-seq and ATAC-seq data. SELMA can utilize internal mitochondrial DNA data to improve bias estimation. We show that transcription factor binding inference from DNase footprints can be improved by incorporating estimated biases using SELMA. Furthermore, we show strong effects of intrinsic biases in single-cell ATAC-seq data, and develop the first single-cell ATAC-seq intrinsic bias correction model to improve cell clustering. SELMA can enhance the performance of existing bioinformatics tools and improve the analysis of both bulk and single-cell chromatin accessibility sequencing data.
    DOI:  https://doi.org/10.1038/s41467-022-33194-z
  10. Nat Commun. 2022 Sep 23. 13(1): 5594
    Activation of the insulin receptor by an insulin mimetic peptide.
    Junhee Park, Jie Li, John P Mayer, Kerri A Ball, Jiayi Wu, Catherine Hall, Domenico Accili, Michael H B Stowell, Xiao-Chen Bai, Eunhee Choi.
      Insulin receptor (IR) signaling defects cause a variety of metabolic diseases including diabetes. Moreover, inherited mutations of the IR cause severe insulin resistance, leading to early morbidity and mortality with limited therapeutic options. A previously reported selective IR agonist without sequence homology to insulin, S597, activates IR and mimics insulin's action on glycemic control. To elucidate the mechanism of IR activation by S597, we determine cryo-EM structures of the mouse IR/S597 complex. Unlike the compact T-shaped active IR resulting from the binding of four insulins to two distinct sites, two S597 molecules induce and stabilize an extended T-shaped IR through the simultaneous binding to both the L1 domain of one protomer and the FnIII-1 domain of another. Importantly, S597 fully activates IR mutants that disrupt insulin binding or destabilize the insulin-induced compact T-shape, thus eliciting insulin-like signaling. S597 also selectively activates IR signaling among different tissues and triggers IR endocytosis in the liver. Overall, our structural and functional studies guide future efforts to develop insulin mimetics targeting insulin resistance caused by defects in insulin binding and stabilization of insulin-activated state of IR, demonstrating the potential of structure-based drug design for insulin-resistant diseases.
    DOI:  https://doi.org/10.1038/s41467-022-33274-0
  11. Nat Commun. 2022 Sep 23. 13(1): 5599
    Cytoplasmic organization promotes protein diffusion in Xenopus extracts.
    William Y C Huang, Xianrui Cheng, James E Ferrell.
      The cytoplasm is highly organized. However, the extent to which this organization influences the dynamics of cytoplasmic proteins is not well understood. Here, we use Xenopus laevis egg extracts as a model system to study diffusion dynamics in organized versus disorganized cytoplasm. Such extracts are initially homogenized and disorganized, and self-organize into cell-like units over the course of tens of minutes. Using fluorescence correlation spectroscopy, we observe that as the cytoplasm organizes, protein diffusion speeds up by about a factor of two over a length scale of a few hundred nanometers, eventually approaching the diffusion time measured in organelle-depleted cytosol. Even though the ordered cytoplasm contained organelles and cytoskeletal elements that might interfere with diffusion, the convergence of protein diffusion in the cytoplasm toward that in organelle-depleted cytosol suggests that subcellular organization maximizes protein diffusivity. The effect of organization on diffusion varies with molecular size, with the effects being largest for protein-sized molecules, and with the time scale of the measurement. These results show that cytoplasmic organization promotes the efficient diffusion of protein molecules in a densely packed environment.
    DOI:  https://doi.org/10.1038/s41467-022-33339-0
  12. Nat Commun. 2022 Sep 20. 13(1): 5504
    Learning enhances encoding of time and temporal surprise in mouse primary sensory cortex.
    Rebecca J Rabinovich, Daniel D Kato, Randy M Bruno.
      Primary sensory cortex has long been believed to play a straightforward role in the initial processing of sensory information. Yet, the superficial layers of cortex overall are sparsely active, even during sensory stimulation; additionally, cortical activity is influenced by other modalities, task context, reward, and behavioral state. Our study demonstrates that reinforcement learning dramatically alters representations among longitudinally imaged neurons in superficial layers of mouse primary somatosensory cortex. Learning an object detection task recruits previously unresponsive neurons, enlarging the neuronal population sensitive to touch and behavioral choice. Cortical responses decrease upon repeated stimulus presentation outside of the behavioral task. Moreover, training improves population encoding of the passage of time, and unexpected deviations in trial timing elicit even stronger responses than touches do. In conclusion, the superficial layers of sensory cortex exhibit a high degree of learning-dependent plasticity and are strongly modulated by non-sensory but behaviorally-relevant features, such as timing and surprise.
    DOI:  https://doi.org/10.1038/s41467-022-33141-y
  13. Nat Commun. 2022 Sep 23. 13(1): 5584
    Intracellular energy controls dynamics of stress-induced ribonucleoprotein granules.
    Tao Wang, Xibin Tian, Han Byeol Kim, Yura Jang, Zhiyuan Huang, Chan Hyun Na, Jiou Wang.
      Energy metabolism and membraneless organelles have been implicated in human diseases including neurodegeneration. How energy deficiency regulates ribonucleoprotein particles such as stress granules (SGs) is still unclear. Here we identified a unique type of granules induced by energy deficiency under physiological conditions and uncovered the mechanisms by which the dynamics of diverse stress-induced granules are regulated. Severe energy deficiency induced the rapid formation of energy deficiency-induced stress granules (eSGs) independently of eIF2α phosphorylation, whereas moderate energy deficiency delayed the clearance of conventional SGs. The formation of eSGs or the clearance of SGs was regulated by the mTOR-4EBP1-eIF4E pathway or eIF4A1, involving assembly of the eIF4F complex or RNA condensation, respectively. In neurons or brain organoids derived from patients carrying the C9orf72 repeat expansion associated with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), the eSG formation was enhanced, and the clearance of conventional SGs was impaired. These results reveal a critical role for intracellular energy in the regulation of diverse granules and suggest that disruptions in energy-controlled granule dynamics may contribute to the pathogenesis of relevant diseases.
    DOI:  https://doi.org/10.1038/s41467-022-33079-1
  14. Nat Commun. 2022 Sep 17. 13(1): 5461
    Single-cell transcriptomics reveal cellular diversity of aortic valve and the immunomodulation by PPARγ during hyperlipidemia.
    Seung Hyun Lee, Nayoung Kim, Minkyu Kim, Sang-Ho Woo, Inhee Han, Jisu Park, Kyeongdae Kim, Kyu Seong Park, Kibyeong Kim, Dahee Shim, Sang-Eun Park, Jing Yu Zhang, Du-Min Go, Dae-Yong Kim, Won Kee Yoon, Seung-Pyo Lee, Jongsuk Chung, Ki-Wook Kim, Jung Hwan Park, Seung Hyun Lee, Sak Lee, Soo-Jin Ann, Sang-Hak Lee, Hyo-Suk Ahn, Seong Cheol Jeong, Tae Kyeong Kim, Goo Taeg Oh, Woong-Yang Park, Hae-Ock Lee, Jae-Hoon Choi.
      Valvular inflammation triggered by hyperlipidemia has been considered as an important initial process of aortic valve disease; however, cellular and molecular evidence remains unclear. Here, we assess the relationship between plasma lipids and valvular inflammation, and identify association of low-density lipoprotein with increased valvular lipid and macrophage accumulation. Single-cell RNA sequencing analysis reveals the cellular heterogeneity of leukocytes, valvular interstitial cells, and valvular endothelial cells, and their phenotypic changes during hyperlipidemia leading to recruitment of monocyte-derived MHC-IIhi macrophages. Interestingly, we find activated PPARγ pathway in Cd36+ valvular endothelial cells increased in hyperlipidemic mice, and the conservation of PPARγ activation in non-calcified human aortic valves. While the PPARγ inhibition promotes inflammation, PPARγ activation using pioglitazone reduces valvular inflammation in hyperlipidemic mice. These results show that low-density lipoprotein is the main lipoprotein accumulated in the aortic valve during hyperlipidemia, leading to early-stage aortic valve disease, and PPARγ activation protects the aortic valve against inflammation.
    DOI:  https://doi.org/10.1038/s41467-022-33202-2
  15. Nat Methods. 2022 Sep 22.
    Cell region fingerprints enable highly precise single-cell tracking and lineage reconstruction.
    Andreas P Cuny, Aaron Ponti, Tomas Kündig, Fabian Rudolf, Jörg Stelling.
      Experimental studies of cell growth, inheritance and their associated processes by microscopy require accurate single-cell observations of sufficient duration to reconstruct the genealogy. However, cell tracking-assigning identical cells on consecutive images to a track-is often challenging, resulting in laborious manual verification. Here, we propose fingerprints to identify problematic assignments rapidly. A fingerprint distance compares the structural information contained in the low frequencies of a Fourier transform to measure the similarity between cells in two consecutive images. We show that fingerprints are broadly applicable across cell types and image modalities, provided the image has sufficient structural information. Our tracker (TracX) uses fingerprints to reject unlikely assignments, thereby increasing tracking performance on published and newly generated long-term data sets. For Saccharomyces cerevisiae, we propose a comprehensive model for cell size control at the single-cell and population level centered on the Whi5 regulator, demonstrating how precise tracking can help uncover previously undescribed single-cell biology.
    DOI:  https://doi.org/10.1038/s41592-022-01603-2
  16. Nat Commun. 2022 Sep 23. 13(1): 5562
    Revisiting life history and morphological proxies for early mammaliaform metabolic rates.
    Shai Meiri, Eran Levin.
      
    DOI:  https://doi.org/10.1038/s41467-022-32715-0
  17. Nat Immunol. 2022 Sep 22.
    Cellular and transcriptional dynamics of human neutrophils at steady state and upon stress.
    Elisa Montaldo, Eleonora Lusito, Valentina Bianchessi, Nicoletta Caronni, Serena Scala, Luca Basso-Ricci, Carla Cantaffa, Alice Masserdotti, Mattia Barilaro, Simona Barresi, Marco Genua, Francesco Maria Vittoria, Giulia Barbiera, Dejan Lazarevic, Carlo Messina, Elisabetta Xue, Sarah Marktel, Cristina Tresoldi, Raffaella Milani, Paola Ronchi, Salvatore Gattillo, Luca Santoleri, Raffaella Di Micco, Andrea Ditadi, Giulio Belfiori, Francesca Aleotti, Matteo Maria Naldini, Bernhard Gentner, Elisa Gardiman, Nicola Tamassia, Marco Antonio Cassatella, Andrés Hidalgo, Immanuel Kwok, Lai Guan Ng, Stefano Crippa, Massimo Falconi, Francesca Pettinella, Patrizia Scapini, Luigi Naldini, Fabio Ciceri, Alessandro Aiuti, Renato Ostuni.
      Traditionally viewed as poorly plastic, neutrophils are now recognized as functionally diverse; however, the extent and determinants of neutrophil heterogeneity in humans remain unclear. We performed a comprehensive immunophenotypic and transcriptome analysis, at a bulk and single-cell level, of neutrophils from healthy donors and patients undergoing stress myelopoiesis upon exposure to growth factors, transplantation of hematopoietic stem cells (HSC-T), development of pancreatic cancer and viral infection. We uncover an extreme diversity of human neutrophils in vivo, reflecting the rates of cell mobilization, differentiation and exposure to environmental signals. Integrated control of developmental and inducible transcriptional programs linked flexible granulopoietic outputs with elicitation of stimulus-specific functional responses. In this context, we detected an acute interferon (IFN) response in the blood of patients receiving HSC-T that was mirrored by marked upregulation of IFN-stimulated genes in neutrophils but not in monocytes. Systematic characterization of human neutrophil plasticity may uncover clinically relevant biomarkers and support the development of diagnostic and therapeutic tools.
    DOI:  https://doi.org/10.1038/s41590-022-01311-1
  18. Nat Genet. 2022 Sep 19.
    The evolutionary dynamics of extrachromosomal DNA in human cancers.
    Joshua T Lange, John C Rose, Celine Y Chen, Yuriy Pichugin, Liangqi Xie, Jun Tang, King L Hung, Kathryn E Yost, Quanming Shi, Marcella L Erb, Utkrisht Rajkumar, Sihan Wu, Sabine Taschner-Mandl, Marie Bernkopf, Charles Swanton, Zhe Liu, Weini Huang, Howard Y Chang, Vineet Bafna, Anton G Henssen, Benjamin Werner, Paul S Mischel.
      Oncogene amplification on extrachromosomal DNA (ecDNA) is a common event, driving aggressive tumor growth, drug resistance and shorter survival. Currently, the impact of nonchromosomal oncogene inheritance-random identity by descent-is poorly understood. Also unclear is the impact of ecDNA on somatic variation and selection. Here integrating theoretical models of random segregation, unbiased image analysis, CRISPR-based ecDNA tagging with live-cell imaging and CRISPR-C, we demonstrate that random ecDNA inheritance results in extensive intratumoral ecDNA copy number heterogeneity and rapid adaptation to metabolic stress and targeted treatment. Observed ecDNAs benefit host cell survival or growth and can change within a single cell cycle. ecDNA inheritance can predict, a priori, some of the aggressive features of ecDNA-containing cancers. These properties are facilitated by the ability of ecDNA to rapidly adapt genomes in a way that is not possible through chromosomal oncogene amplification. These results show how the nonchromosomal random inheritance pattern of ecDNA contributes to poor outcomes for patients with cancer.
    DOI:  https://doi.org/10.1038/s41588-022-01177-x
  19. Nat Commun. 2022 Sep 21. 13(1): 5529
    Differential dysregulation of granule subsets in WASH-deficient neutrophil leukocytes resulting in inflammation.
    Jennifer L Johnson, Elsa Meneses-Salas, Mahalakshmi Ramadass, Jlenia Monfregola, Farhana Rahman, Raquel Carvalho Gontijo, William B Kiosses, Kersi Pestonjamasp, Dale Allen, Jinzhong Zhang, Douglas G Osborne, Yanfang Peipei Zhu, Nathan Wineinger, Kasra Askari, Danni Chen, Juan Yu, Scott C Henderson, Catherine C Hedrick, Matilde Valeria Ursini, Sergio Grinstein, Daniel D Billadeau, Sergio D Catz.
      Dysregulated secretion in neutrophil leukocytes associates with human inflammatory disease. The exocytosis response to triggering stimuli is sequential; gelatinase granules modulate the initiation of the innate immune response, followed by the release of pro-inflammatory azurophilic granules, requiring stronger stimulation. Exocytosis requires actin depolymerization which is actively counteracted under non-stimulatory conditions. Here we show that the actin nucleator, WASH, is necessary to maintain azurophilic granules in their refractory state by granule actin entrapment and interference with the Rab27a-JFC1 exocytic machinery. On the contrary, gelatinase granules of WASH-deficient neutrophil leukocytes are characterized by decreased Rac1, shortened granule-associated actin comets and impaired exocytosis. Rac1 activation restores exocytosis of these granules. In vivo, WASH deficiency induces exacerbated azurophilic granule exocytosis, inflammation, and decreased survival. WASH deficiency thus differentially impacts neutrophil granule subtypes, impairing exocytosis of granules that mediate the initiation of the neutrophil innate response while exacerbating pro-inflammatory granule secretion.
    DOI:  https://doi.org/10.1038/s41467-022-33230-y
  20. Commun Biol. 2022 Sep 21. 5(1): 1002
    miR204 potentially promotes non-alcoholic fatty liver disease by inhibition of cpt1a in mouse hepatocytes.
    Seonhee Kim, Ikjun Lee, Shuyu Piao, Harsha Nagar, Su-Jeong Choi, Young-Rae Kim, Kaikobad Irani, Byeong Hwa Jeon, Cuk-Seong Kim.
      Non-alcoholic fatty liver disease (NAFLD) is associated with hepatic metabolism dysfunction. However, the mechanistic role of miR204 in the development of NAFLD is unknown. We investigate the functional significance of miR204 in the evolution of NAFLD. IDH2 KO mice feed a normal diet (ND) or HFD increased body weight, epididymal fat-pad weight, lipid droplet in liver, blood parameter and inflammation compared to WT mice fed a ND or HFD. Moreover, the expression of miR204 is increased in mice with IDH2 deficiency. Increased miR204 by IDH2 deficiency regulates carnitine palmitoyltransferase 1a (cpt1a) synthesis, which inhibits fatty acid β-oxidation. Inhibition of miR204 prevents the disassembly of two fatty acid-related genes by activating CPT1a expression, which decreases lipid droplet in liver, inflammatory cytokines, epididymal fat pad weight, blood parameters. Increased miR204 by IDH2 deficiency promotes the pathogenesis of HFD-induced NAFLD by regulating hepatic fatty acid metabolism and inflammation.
    DOI:  https://doi.org/10.1038/s42003-022-03945-1
  21. Aging Cell. 2022 Sep 18. e13713
    Reduced endosomal microautophagy activity in aging associates with enhanced exocyst-mediated protein secretion.
    Gregory J Krause, Antonio Diaz, Maryam Jafari, Rabia R Khawaja, Esperanza Agullo-Pascual, Olaya Santiago-Fernández, Alicia L Richards, Kuei-Ho Chen, Phillip Dmitriev, Yan Sun, Stephanie K See, Kotb Abdelmohsen, Krystyna Mazan-Mamczarz, Nevan J Krogan, Myriam Gorospe, Danielle L Swaney, Simone Sidoli, Jose Javier Bravo-Cordero, Martin Kampmann, Ana Maria Cuervo.
      Autophagy is essential for protein quality control and regulation of the functional proteome. Failure of autophagy pathways with age contributes to loss of proteostasis in aged organisms and accelerates the progression of age-related diseases. In this work, we show that activity of endosomal microautophagy (eMI), a selective type of autophagy occurring in late endosomes, declines with age and identify the sub-proteome affected by this loss of function. Proteomics of late endosomes from old mice revealed an aberrant glycation signature for Hsc70, the chaperone responsible for substrate targeting to eMI. Age-related Hsc70 glycation reduces its stability in late endosomes by favoring its organization into high molecular weight protein complexes and promoting its internalization/degradation inside late endosomes. Reduction of eMI with age associates with an increase in protein secretion, as late endosomes can release protein-loaded exosomes upon plasma membrane fusion. Our search for molecular mediators of the eMI/secretion switch identified the exocyst-RalA complex, known for its role in exocytosis, as a novel physiological eMI inhibitor that interacts with Hsc70 and acts directly at the late endosome membrane. This inhibitory function along with the higher exocyst-RalA complex levels detected in late endosomes from old mice could explain, at least in part, reduced eMI activity with age. Interaction of Hsc70 with components of the exocyst-RalA complex places this chaperone in the switch from eMI to secretion. Reduced intracellular degradation in favor of extracellular release of undegraded material with age may be relevant to the spreading of proteotoxicity associated with aging and progression of proteinopathies.
    Keywords:  aging; autophagy; chaperones; endosomal microautophagy; exocyst complex; late endosomes; protein secretion; proteostasis
    DOI:  https://doi.org/10.1111/acel.13713
  22. Nat Immunol. 2022 Sep 23.
    m1A tRNA modification facilitates rapid T cell proliferation.
      
    DOI:  https://doi.org/10.1038/s41590-022-01302-2
  23. J Immunol. 2022 Sep 01. 209(5): 926-937
    APRIL Drives a Coordinated but Diverse Response as a Foundation for Plasma Cell Longevity.
    Sophie Stephenson, Matthew A Care, Gina M Doody, Reuben M Tooze.
      Ab-secreting cells survive in niche microenvironments, but cellular responses driven by particular niche signals are incompletely defined. The TNF superfamily member a proliferation-inducing ligand (APRIL) can support the maturation of transitory plasmablasts into long-lived plasma cells. In this study, we explore the biological programs established by APRIL in human plasmablasts. Under conditions allowing the maturation of ex vivo- or in vitro-generated plasmablasts, we find that APRIL drives activation of ERK, p38, and JNK, accompanied by a classical NF-κB response and activation of the AKT/FOXO1 pathway. Time-course gene expression data resolve coordinated transcriptional responses propagated via immediate early genes and NF-κB targets and converging onto modules of genes enriched for MYC targets and metabolism/cell growth-related pathways. This response is shared between APRIL and an alternate TNF superfamily member CD40L but is not a feature of alternative niche signals delivered by IFN-α or SDF1. However, APRIL and CD40L responses also diverge. CD40L drives expression of genes related to the activated B cell state whereas APRIL does not. Thus, APRIL establishes a broad foundation for plasma cell longevity with features of cellular refueling while being uncoupled from support of the B cell state.
    DOI:  https://doi.org/10.4049/jimmunol.2100623
  24. Nat Commun. 2022 09 20. 13(1): 4983
    Diabetes downregulates the antimicrobial peptide psoriasin and increases E. coli burden in the urinary bladder.
    Soumitra Mohanty, Witchuda Kamolvit, Andrea Scheffschick, Anneli Björklund, Jonas Tovi, Alexander Espinosa, Kerstin Brismar, Thomas Nyström, Jens M Schröder, Claes-Göran Östenson, Pontus Aspenström, Hanna Brauner, Annelie Brauner.
      Diabetes is known to increase susceptibility to infections, partly due to impaired granulocyte function and changes in the innate immunity. Here, we investigate the effect of diabetes, and high glucose on the expression of the antimicrobial peptide, psoriasin and the putative consequences for E. coli urinary tract infection. Blood, urine, and urine exfoliated cells from patients are studied. The influence of glucose and insulin is examined during hyperglycemic clamps in individuals with prediabetes and in euglycemic hyperinsulinemic clamped patients with type 1 diabetes. Important findings are confirmed in vivo in type 2 diabetic mice and verified in human uroepithelial cell lines. High glucose concentrations induce lower psoriasin levels and impair epithelial barrier function together with altering cell membrane proteins and cytoskeletal elements, resulting in increasing bacterial burden. Estradiol treatment restores the cellular function with increasing psoriasin and bacterial killing in uroepithelial cells, confirming its importance during urinary tract infection in hyperglycemia. In conclusion, our findings present the effects and underlying mechanisms of high glucose compromising innate immunity.
    DOI:  https://doi.org/10.1038/s41467-022-32636-y
  25. Sci Adv. 2022 Sep 23. 8(38): eabm6668
    Apolipoprotein E mediates cell resistance to influenza virus infection.
    Ping Gao, Miao Ji, Xinyuan Liu, Xiaotong Chen, Hongtao Liu, Shihua Li, Baoqian Jia, Chao Li, Lili Ren, Xin Zhao, Qihui Wang, Yuhai Bi, Xu Tan, Baidong Hou, Xuyu Zhou, Wenjie Tan, Tao Deng, Jianwei Wang, George Fu Gao, Fuping Zhang.
      Viruses exploit host cell machinery to support their replication. Defining the cellular proteins and processes required for a virus during infection is crucial to understanding the mechanisms of virally induced disease and designing host-directed therapeutics. Here, we perform a genome-wide CRISPR-Cas9-based screening in lung epithelial cells infected with the PR/8/NS1-GFP virus and use GFPhi cell as a unique screening marker to identify host factors that inhibit influenza A virus (IAV) infection. We discovered that APOE affects influenza virus infection both in vitro and in vivo. Cell deficiency in APOE conferred substantially increased susceptibility to IAV; mice deficient in APOE manifested more severe lung pathology, increased virus load, and decreased survival rate. Mechanistically, lack of cell-produced APOE results in impaired cell cholesterol homeostasis, enhancing influenza virus attachment. Thus, we identified a previously unrecognized role of APOE in restraining IAV infection.
    DOI:  https://doi.org/10.1126/sciadv.abm6668
  26. J Immunol. 2022 Sep 15. 209(6): 1025-1032
    CTLs Get SMAD When Pathogens Tell Them Where to Go.
    Jenny E Suarez-Ramirez, Linda S Cauley, Karthik Chandiran.
      Vaccines protect against infections by eliciting both Ab and T cell responses. Because the immunity wanes as protective epitopes get modified by accruing mutations, developing strategies for immunization against new variants is a major priority for vaccine development. CTLs eliminate cells that support viral replication and provide protection against new variants by targeting epitopes from internal viral proteins. This form of protection has received limited attention during vaccine development, partly because reliable methods for directing pathogen-specific memory CD8 T cells to vulnerable tissues are currently unavailable. In this review we examine how recent studies expand our knowledge of mechanisms that contribute to the functional diversity of CTLs as they respond to infection. We discuss the role of TGF-β and the SMAD signaling cascade during genetic programming of pathogen-specific CTLs and the pathways that promote formation of a newly identified subset of terminally differentiated memory CD8 T cells that localize in the vasculature.
    DOI:  https://doi.org/10.4049/jimmunol.2200345
  27. Nat Immunol. 2022 Sep 22.
    NUDT21 limits CD19 levels through alternative mRNA polyadenylation in B cell acute lymphoblastic leukemia.
    Matthew T Witkowski, Soobeom Lee, Eric Wang, Anna K Lee, Alexis Talbot, Chao Ma, Nikolaos Tsopoulidis, Justin Brumbaugh, Yaqi Zhao, Kathryn G Roberts, Simon J Hogg, Sofia Nomikou, Yohana E Ghebrechristos, Palaniraja Thandapani, Charles G Mullighan, Konrad Hochedlinger, Weiqiang Chen, Omar Abdel-Wahab, Justin Eyquem, Iannis Aifantis.
      B cell progenitor acute lymphoblastic leukemia (B-ALL) treatment has been revolutionized by T cell-based immunotherapies-including chimeric antigen receptor T cell therapy (CAR-T) and the bispecific T cell engager therapeutic, blinatumomab-targeting surface glycoprotein CD19. Unfortunately, many patients with B-ALL will fail immunotherapy due to 'antigen escape'-the loss or absence of leukemic CD19 targeted by anti-leukemic T cells. In the present study, we utilized a genome-wide CRISPR-Cas9 screening approach to identify modulators of CD19 abundance on human B-ALL blasts. These studies identified a critical role for the transcriptional activator ZNF143 in CD19 promoter activation. Conversely, the RNA-binding protein, NUDT21, limited expression of CD19 by regulating CD19 messenger RNA polyadenylation and stability. NUDT21 deletion in B-ALL cells increased the expression of CD19 and the sensitivity to CD19-specific CAR-T and blinatumomab. In human B-ALL patients treated with CAR-T and blinatumomab, upregulation of NUDT21 mRNA coincided with CD19 loss at disease relapse. Together, these studies identify new CD19 modulators in human B-ALL.
    DOI:  https://doi.org/10.1038/s41590-022-01314-y
  28. Nat Commun. 2022 Sep 23. 13(1): 5595
    Bacterial diet modulates tamoxifen-induced death via host fatty acid metabolism.
    Cédric Diot, Aurian P García-González, Andre F Vieira, Melissa Walker, Megan Honeywell, Hailey Doyle, Olga Ponomarova, Yomari Rivera, Huimin Na, Hefei Zhang, Michael Lee, Carissa P Olsen, Albertha J M Walhout.
      Tamoxifen is a selective estrogen receptor (ER) modulator that is used to treat ER-positive breast cancer, but that at high doses kills both ER-positive and ER-negative breast cancer cells. We recapitulate this off-target effect in Caenorhabditis elegans, which does not have an ER ortholog. We find that different bacteria dramatically modulate tamoxifen toxicity in C. elegans, with a three-order of magnitude difference between animals fed Escherichia coli, Comamonas aquatica, and Bacillus subtilis. Remarkably, host fatty acid (FA) biosynthesis mitigates tamoxifen toxicity, and different bacteria provide the animal with different FAs, resulting in distinct FA profiles. Surprisingly these bacteria modulate tamoxifen toxicity by different death mechanisms, some of which are modulated by FA supplementation and others by antioxidants. Together, this work reveals a complex interplay between microbiota, FA metabolism and tamoxifen toxicity that may provide a blueprint for similar studies in more complex mammals.
    DOI:  https://doi.org/10.1038/s41467-022-33299-5
  29. Nat Commun. 2022 Sep 22. 13(1): 5565
    Ubiquitination of CLIP-170 family protein restrains polarized growth upon DNA replication stress.
    Xi Wang, Fan Zheng, Yuan-Yuan Yi, Gao-Yuan Wang, Li-Xin Hong, Dannel McCollum, Chuanhai Fu, Yamei Wang, Quan-Wen Jin.
      Microtubules play a crucial role during the establishment and maintenance of cell polarity. In fission yeast cells, the microtubule plus-end tracking proteins (+TIPs) (including the CLIP-170 homologue Tip1) regulate microtubule dynamics and also transport polarity factors to the cell cortex. Here, we show that the E3 ubiquitin ligase Dma1 plays an unexpected role in controlling polarized growth through ubiquitinating Tip1. Dma1 colocalizes with Tip1 to cortical sites at cell ends, and is required for ubiquitination of Tip1. Although the absence of dma1+ does not cause apparent polar growth defects in vegetatively growing cells, Dma1-mediated Tip1 ubiquitination is required to restrain polar growth upon DNA replication stress. This mechanism is distinct from the previously recognized calcineurin-dependent inhibition of polarized growth. In this work, we establish a link between Dma1-mediated Tip1 ubiquitination and DNA replication or DNA damage checkpoint-dependent inhibition of polarized growth in fission yeast.
    DOI:  https://doi.org/10.1038/s41467-022-33311-y
  30. Nature. 2022 Sep 21.
    A cellular hierarchy in melanoma uncouples growth and metastasis.
    Panagiotis Karras, Ignacio Bordeu, Joanna Pozniak, Ada Nowosad, Cecilia Pazzi, Nina Van Raemdonck, Ewout Landeloos, Yannick Van Herck, Dennis Pedri, Greet Bervoets, Samira Makhzami, Jia Hui Khoo, Benjamin Pavie, Jochen Lamote, Oskar Marin-Bejar, Michael Dewaele, Han Liang, Xingju Zhang, Yichao Hua, Jasper Wouters, Robin Browaeys, Gabriele Bergers, Yvan Saeys, Francesca Bosisio, Joost van den Oord, Diether Lambrechts, Anil K Rustgi, Oliver Bechter, Cedric Blanpain, Benjamin D Simons, Florian Rambow, Jean-Christophe Marine.
      Although melanoma is notorious for its high degree of heterogeneity and plasticity1,2, the origin and magnitude of cell-state diversity remains poorly understood. Equally, it is unclear whether growth and metastatic dissemination are supported by overlapping or distinct melanoma subpopulations. Here, by combining mouse genetics, single-cell and spatial transcriptomics, lineage tracing and quantitative modelling, we provide evidence of a hierarchical model of tumour growth that mirrors the cellular and molecular logic underlying the cell-fate specification and differentiation of the embryonic neural crest. We show that tumorigenic competence is associated with a spatially localized perivascular niche, a phenotype acquired through an intercellular communication pathway established by endothelial cells. Consistent with a model in which only a fraction of cells are fated to fuel growth, temporal single-cell tracing of a population of melanoma cells with a mesenchymal-like state revealed that these cells do not contribute to primary tumour growth but, instead, constitute a pool of metastatic initiating cells that switch cell identity while disseminating to secondary organs. Our data provide a spatially and temporally resolved map of the diversity and trajectories of melanoma cell states and suggest that the ability to support growth and metastasis are limited to distinct pools of cells. The observation that these phenotypic competencies can be dynamically acquired after exposure to specific niche signals warrant the development of therapeutic strategies that interfere with the cancer cell reprogramming activity of such microenvironmental cues.
    DOI:  https://doi.org/10.1038/s41586-022-05242-7
  31. Nature. 2022 Sep 21.
    Long-primed germinal centres with enduring affinity maturation and clonal migration.
    Jeong Hyun Lee, Henry J Sutton, Christopher A Cottrell, Ivy Phung, Gabriel Ozorowski, Leigh M Sewall, Rebecca Nedellec, Catherine Nakao, Murillo Silva, Sara T Richey, Jonathan L Torre, Wen-Hsin Lee, Erik Georgeson, Michael Kubitz, Sam Hodges, Tina-Marie Mullen, Yumiko Adachi, Kimberly M Cirelli, Amitinder Kaur, Carolina Allers, Marissa Fahlberg, Brooke F Grasperge, Jason P Dufour, Faith Schiro, Pyone P Aye, Oleksandr Kalyuzhniy, Alessia Liguori, Diane G Carnathan, Guido Silvestri, Xiaoying Shen, David C Montefiori, Ronald S Veazey, Andrew B Ward, Lars Hangartner, Dennis R Burton, Darrell J Irvine, William R Schief, Shane Crotty.
      Germinal centres are the engines of antibody evolution. Here, using human immunodeficiency virus (HIV) Env protein immunogen priming in rhesus monkeys followed by a long period without further immunization, we demonstrate germinal centre B (BGC) cells that last for at least 6 months. A 186-fold increase in BGC cells was present by week 10 compared with conventional immunization. Single-cell transcriptional profiling showed that both light- and dark-zone germinal centre states were sustained. Antibody somatic hypermutation of BGC cells continued to accumulate throughout the 29-week priming period, with evidence of selective pressure. Env-binding BGC cells were still 49-fold above baseline at 29 weeks, which suggests that they could remain active for even longer periods of time. High titres of HIV-neutralizing antibodies were generated after a single booster immunization. Fully glycosylated HIV trimer protein is a complex antigen, posing considerable immunodominance challenges for B cells1,2. Memory B cells generated under these long priming conditions had higher levels of antibody somatic hypermutation, and both memory B cells and antibodies were more likely to recognize non-immunodominant epitopes. Numerous BGC cell lineage phylogenies spanning more than the 6-month germinal centre period were identified, demonstrating continuous germinal centre activity and selection for at least 191 days with no further antigen exposure. A long-prime, slow-delivery (12 days) immunization approach holds promise for difficult vaccine targets and suggests that patience can have great value for tuning of germinal centres to maximize antibody responses.
    DOI:  https://doi.org/10.1038/s41586-022-05216-9
  32. Nat Immunol. 2022 Sep 22.
    Single-cell profiling identifies mechanisms of inflammatory heterogeneity in chronic rhinosinusitis.
    Weiqing Wang, Yi Xu, Lun Wang, Zhenzhen Zhu, Surita Aodeng, Hui Chen, Menghua Cai, Zhihao Huang, Jinbo Han, Lei Wang, Yuxi Lin, Yu Hu, Liangrui Zhou, Xiaowei Wang, Yang Zha, Weihong Jiang, Zhiqiang Gao, Wei He, Wei Lv, Jianmin Zhang.
      The heterogeneous cellular microenvironment of human airway chronic inflammatory diseases, including chronic rhinosinusitis (CRS) and asthma, is still poorly understood. Here, we performed single-cell RNA sequencing (scRNA-seq) on the nasal mucosa of healthy individuals and patients with three subtypes of CRS and identified disease-specific cell subsets and molecules that specifically contribute to the pathogenesis of CRS subtypes. As such, ALOX15+ macrophages contributed to the type 2 immunity-driven pathogenesis of one subtype of CRS, eosinophilic CRS with nasal polyps (eCRSwNP), by secreting chemokines that recruited eosinophils, monocytes and T helper 2 (TH2) cells. An inhibitor of ALOX15 reduced the release of proinflammatory chemokines in human macrophages and inhibited the overactivation of type 2 immunity in a mouse model of eosinophilic rhinosinusitis. Our findings advance the understanding of the heterogeneous immune microenvironment and the pathogenesis of CRS subtypes and identify potential therapeutic approaches for the treatment of CRS and potentially other type 2 immunity-mediated diseases.
    DOI:  https://doi.org/10.1038/s41590-022-01312-0
  33. JCI Insight. 2022 Sep 22. pii: e159286. [Epub ahead of print]7(18):
    Flow pattern-dependent mitochondrial dynamics regulates the metabolic profile and inflammatory state of endothelial cells.
    Soon-Gook Hong, Junchul Shin, Soo Young Choi, Jeffery C Powers, Benjamin M Meister, Jacqueline Sayoc, Jun Seok Son, Ryan Tierney, Fabio A Recchia, Michael D Brown, Xiaofeng Yang, Joon-Young Park.
      Endothelial mitochondria play a pivotal role in maintaining endothelial cell (EC) homeostasis through constantly altering their size, shape, and intracellular localization. Studies show that the disruption of the basal mitochondrial network in EC, forming excess fragmented mitochondria, implicates cardiovascular disease. However, cellular consequences underlying the morphological changes in the endothelial mitochondria under distinctively different, but physiologically occurring, flow patterns (i.e., unidirectional flow [UF] versus disturbed flow [DF]) are largely unknown. The purpose of this study was to investigate the effect of different flow patterns on mitochondrial morphology and its implications in EC phenotypes. We show that mitochondrial fragmentation is increased at DF-exposed vessel regions, where elongated mitochondria are predominant in the endothelium of UF-exposed regions. DF increased dynamin-related protein 1 (Drp1), mitochondrial reactive oxygen species (mtROS), hypoxia-inducible factor 1, glycolysis, and EC activation. Inhibition of Drp1 significantly attenuated these phenotypes. Carotid artery ligation and microfluidics experiments further validate that the significant induction of mitochondrial fragmentation was associated with EC activation in a Drp1-dependent manner. Contrarily, UF in vitro or voluntary exercise in vivo significantly decreased mitochondrial fragmentation and enhanced fatty acid uptake and OXPHOS. Our data suggest that flow patterns profoundly change mitochondrial fusion/fission events, and this change contributes to the determination of proinflammatory and metabolic states of ECs.
    Keywords:  Atherosclerosis; Endothelial cells; Mitochondria; Vascular Biology
    DOI:  https://doi.org/10.1172/jci.insight.159286
  34. Nat Commun. 2022 Sep 22. 13(1): 5554
    Chromatin organizer SATB1 controls the cell identity of CD4+ CD8+ double-positive thymocytes by regulating the activity of super-enhancers.
    Delong Feng, Yanhong Chen, Ranran Dai, Shasha Bian, Wei Xue, Yongchang Zhu, Zhaoqiang Li, Yiting Yang, Yan Zhang, Jiarui Zhang, Jie Bai, Litao Qin, Yoshinori Kohwi, Weili Shi, Terumi Kohwi-Shigematsu, Jing Ma, Shixiu Liao, Bingtao Hao.
      CD4+ and CD8+ double-positive (DP) thymocytes play a crucial role in T cell development in the thymus. DP cells rearrange the T cell receptor gene Tcra to generate T cell receptors with TCRβ. DP cells differentiate into CD4 or CD8 single-positive (SP) thymocytes, regulatory T cells, or invariant nature kill T cells (iNKT) in response to TCR signaling. Chromatin organizer SATB1 is highly expressed in DP cells and is essential in regulating Tcra rearrangement and differentiation of DP cells. Here we explored the mechanism of SATB1 orchestrating gene expression in DP cells. Single-cell RNA sequencing shows that Satb1 deletion changes the cell identity of DP thymocytes and down-regulates genes specifically and highly expressed in DP cells. Super-enhancers regulate the expressions of DP-specific genes, and our Hi-C data show that SATB1 deficiency in thymocytes reduces super-enhancer activity by specifically decreasing interactions among super-enhancers and between super-enhancers and promoters. Our results reveal that SATB1 plays a critical role in thymocyte development to promote the establishment of DP cell identity by globally regulating super-enhancers of DP cells at the chromatin architectural level.
    DOI:  https://doi.org/10.1038/s41467-022-33333-6
  35. JCI Insight. 2022 Sep 20. pii: e162290. [Epub ahead of print]
    Blockade of TGF-β signaling reactivates HIV-1/SIV reservoirs and immune responses in vivo.
    Sadia Samer, Yanique Thomas, Mariluz Araínga, Crystal Carter, Lisa M Shirreff, Muhammad S Arif, Juan M Avita, Ines Frank, Michael D McRaven, Christopher T Thuruthiyil, Veli B Heybeli, Meegan R Anderson, Benjamin Owen, Arsen Gaisin, Deepanwita Bose, Lacy M Simons, Judd F Hultquist, James Arthos, Claudia Cicala, Irini Sereti, Philip J Santangelo, Ramon Lorenzo-Redondo, Thomas J Hope, Francois Villinger, Elena Martinelli.
      TGF-β plays a critical role in maintaining immune cells in a resting state by inhibiting cell activation and proliferation. Resting HIV-1 target cells represent the main cellular reservoir after long-term ART. We hypothesized that releasing cells from TGF-β-driven signaling would promote latency reversal. To test our hypothesis, we compared HIV-1 latency models with and without TGF-β and a TGF-β-Type-1 receptor (TGFBR1) inhibitor, galunisertib. We tested the effect of galunisertib in SIV-infected, ART-treated macaques by monitoring SIV-env expression via PET/CT using the Cu64-anti-gp120 Fab(7D3) probe, along with plasma and tissue viral loads (VL). Exogenous TGF-β reduced HIV-1 reactivation in U1 and ACH2 models. Galunisertib increased HIV-1 latency reversal ex vivo and in PBMC from HIV-1 infected, ART-treated aviremic donors. In vivo, oral galunisertib promoted increased total standardized uptake values (SUVtot) in PET/CT images in gut and lymph nodes of 5 out of 7 aviremic, long-term ART-treated, SIV-infected, macaques. This increase correlated with an increase in SIV-RNA in the gut. Two of the 7 animals also exhibited increases in pVL. Higher anti-SIV T cell responses and antibody titers were detected after galunisertib treatment. In summary, our data suggest that blocking TGF-β signaling simultaneously increases retroviral reactivation events and enhances anti-SIV immune responses.
    Keywords:  AIDS/HIV; Cytokines; Immunotherapy; T cells
    DOI:  https://doi.org/10.1172/jci.insight.162290
  36. Cell Rep Med. 2022 Sep 20. pii: S2666-3791(22)00291-9. [Epub ahead of print]3(9): 100742
    High-fructose feeding suppresses cold-stimulated brown adipose tissue glucose uptake independently of changes in thermogenesis and the gut microbiome.
    Gabriel Richard, Denis P Blondin, Saad A Syed, Laura Rossi, Michelle E Fontes, Mélanie Fortin, Serge Phoenix, Frédérique Frisch, Stéphanie Dubreuil, Brigitte Guérin, Éric E Turcotte, Martin Lepage, Michael G Surette, Jonathan D Schertzer, Gregory R Steinberg, Katherine M Morrison, André C Carpentier.
      Diets rich in added sugars are associated with metabolic diseases, and studies have shown a link between these pathologies and changes in the microbiome. Given the reported associations in animal models between the microbiome and brown adipose tissue (BAT) function, and the alterations in the microbiome induced by high-glucose or high-fructose diets, we investigated the potential causal link between high-glucose or -fructose diets and BAT dysfunction in humans. Primary outcomes are changes in BAT cold-induced thermogenesis and the fecal microbiome (clinicaltrials.gov, NCT03188835). We show that BAT glucose uptake, but not thermogenesis, is impaired by a high-fructose but not high-glucose diet, in the absence of changes in the gastrointestinal microbiome. We conclude that decreased BAT glucose metabolism occurs earlier than other pathophysiological abnormalities during fructose overconsumption in humans. This is a potential confounding factor for studies relying on 18F-FDG to assess BAT thermogenesis.
    Keywords:  brown adipose tissue; fructose; glucose; magnetic resonance; metabolic dysfunction; microbiome; overfeeding; positron emission tomography; short-chain fatty acids; stable isotopes
    DOI:  https://doi.org/10.1016/j.xcrm.2022.100742
  37. Hepatology. 2022 Oct;76(4): 901-902
    Hepatology highlights.
    Tiffany Wu, Davide Povero, Gopanandan Parthasarathy, Francisco Idalsoaga, Juan Pablo Arab, Sumera I Ilyas.
      
    DOI:  https://doi.org/10.1002/hep.32683
  38. Nat Commun. 2022 Sep 21. 13(1): 5538
    Multi-omic brain and behavioral correlates of cell-free fetal DNA methylation in macaque maternal obesity models.
    Benjamin I Laufer, Yu Hasegawa, Zhichao Zhang, Casey E Hogrefe, Laura A Del Rosso, Lori Haapanen, Hyeyeon Hwang, Melissa D Bauman, Judy Van de Water, Ameer Y Taha, Carolyn M Slupsky, Mari S Golub, John P Capitanio, Catherine A VandeVoort, Cheryl K Walker, Janine M LaSalle.
      Maternal obesity during pregnancy is associated with neurodevelopmental disorder (NDD) risk. We utilized integrative multi-omics to examine maternal obesity effects on offspring neurodevelopment in rhesus macaques by comparison to lean controls and two interventions. Differentially methylated regions (DMRs) from longitudinal maternal blood-derived cell-free fetal DNA (cffDNA) significantly overlapped with DMRs from infant brain. The DMRs were enriched for neurodevelopmental functions, methylation-sensitive developmental transcription factor motifs, and human NDD DMRs identified from brain and placenta. Brain and cffDNA methylation levels from a large region overlapping mir-663 correlated with maternal obesity, metabolic and immune markers, and infant behavior. A DUX4 hippocampal co-methylation network correlated with maternal obesity, infant behavior, infant hippocampal lipidomic and metabolomic profiles, and maternal blood measurements of DUX4 cffDNA methylation, cytokines, and metabolites. We conclude that in this model, maternal obesity was associated with changes in the infant brain and behavior, and these differences were detectable in pregnancy through integrative analyses of cffDNA methylation with immune and metabolic factors.
    DOI:  https://doi.org/10.1038/s41467-022-33162-7
  39. Nat Commun. 2022 Sep 23. 13(1): 5598
    Live imaging and conditional disruption of native PCP activity using endogenously tagged zebrafish sfGFP-Vangl2.
    Maria Jussila, Curtis W Boswell, Nigel W Griffiths, Patrick G Pumputis, Brian Ciruna.
      Tissue-wide coordination of polarized cytoskeletal organization and cell behaviour, critical for normal development, is controlled by asymmetric membrane localization of non-canonical Wnt/planar cell polarity (PCP) signalling components. Understanding the dynamic regulation of PCP thus requires visualization of these polarity proteins in vivo. Here we utilize CRISPR/Cas9 genome editing to introduce a fluorescent reporter onto the core PCP component, Vangl2, in zebrafish. Through live imaging of endogenous sfGFP-Vangl2 expression, we report on the authentic regulation of vertebrate PCP during embryogenesis. Furthermore, we couple sfGFP-Vangl2 with conditional zGrad GFP-nanobody degradation methodologies to interrogate tissue-specific functions for PCP. Remarkably, loss of Vangl2 in foxj1a-positive cell lineages causes ependymal cell cilia and Reissner fiber formation defects as well as idiopathic-like scoliosis. Together, our studies provide crucial insights into the establishment and maintenance of vertebrate PCP and create a powerful experimental paradigm for investigating post-embryonic and tissue-specific functions for Vangl2 in development and disease.
    DOI:  https://doi.org/10.1038/s41467-022-33322-9
  40. Sci Adv. 2022 Sep 23. 8(38): eabq1799
    The adipocyte-enriched secretory protein tetranectin exacerbates type 2 diabetes by inhibiting insulin secretion from β cells.
    Fen Liu, Zixin Cai, Yan Yang, George Plasko, Piao Zhao, Xiangyue Wu, Cheng Tang, Dandan Li, Ting Li, Shanbiao Hu, Lei Song, Shaojie Yu, Ran Xu, Hairong Luo, Libin Fan, Ersong Wang, Zhen Xiao, Yujiao Ji, Rong Zeng, Rongxia Li, Juli Bai, Zhiguang Zhou, Feng Liu, Jingjing Zhang.
      Pancreatic β cell failure is a hallmark of diabetes. However, the causes of β cell failure remain incomplete. Here, we report the identification of tetranectin (TN), an adipose tissue-enriched secretory molecule, as a negative regulator of insulin secretion in β cells in diabetes. TN expression is stimulated by high glucose in adipocytes via the p38 MAPK/TXNIP/thioredoxin/OCT4 signaling pathway, and elevated serum TN levels are associated with diabetes. TN treatment greatly exacerbates hyperglycemia in mice and suppresses glucose-stimulated insulin secretion in islets. Conversely, knockout of TN or neutralization of TN function notably improves insulin secretion and glucose tolerance in high-fat diet-fed mice. Mechanistically, TN binds with high selectivity to β cells and inhibits insulin secretion by blocking L-type Ca2+ channels. Our study uncovers an adipocyte-β cell cross-talk that contributes to β cell dysfunction in diabetes and suggests that neutralization of TN levels may provide a new treatment strategy for type 2 diabetes.
    DOI:  https://doi.org/10.1126/sciadv.abq1799
  41. Sci Adv. 2022 Sep 23. 8(38): eabn6545
    PD-1/PD-L1 blockade abrogates a dysfunctional innate-adaptive immune axis in critical β-coronavirus disease.
    Maite Duhalde Vega, Daniela Olivera, Gustavo Gastão Davanzo, Mauricio Bertullo, Verónica Noya, Gabriela Fabiano de Souza, Stéfanie Primon Muraro, Icaro Castro, Ana Paula Arévalo, Martina Crispo, Germán Galliussi, Sofía Russo, David Charbonnier, Florencia Rammauro, Mathías Jeldres, Catalina Alamón, Valentina Varela, Carlos Batthyany, Mariela Bollati-Fogolín, Pablo Oppezzo, Otto Pritsch, José Luiz Proença-Módena, Helder I Nakaya, Emiliano Trias, Luis Barbeito, Ignacio Anegon, María Cristina Cuturi, Pedro Moraes-Vieira, Mercedes Segovia, Marcelo Hill.
      Severe COVID-19 is associated with hyperinflammation and weak T cell responses against SARS-CoV-2. However, the links between those processes remain partially characterized. Moreover, whether and how therapeutically manipulating T cells may benefit patients are unknown. Our genetic and pharmacological evidence demonstrates that the ion channel TMEM176B inhibited inflammasome activation triggered by SARS-CoV-2 and SARS-CoV-2-related murine β-coronavirus. Tmem176b-/- mice infected with murine β-coronavirus developed inflammasome-dependent T cell dysfunction and critical disease, which was controlled by modulating dysfunctional T cells with PD-1 blockers. In critical COVID-19, inflammasome activation correlated with dysfunctional T cells and low monocytic TMEM176B expression, whereas PD-L1 blockade rescued T cell functionality. Here, we mechanistically link T cell dysfunction and inflammation, supporting a cancer immunotherapy to reinforce T cell immunity in critical β-coronavirus disease.
    DOI:  https://doi.org/10.1126/sciadv.abn6545
  42. Nat Commun. 2022 Sep 17. 13(1): 5464
    Mechanistic understanding of human SLFN11.
    Felix J Metzner, Simon J Wenzl, Michael Kugler, Stefan Krebs, Karl-Peter Hopfner, Katja Lammens.
      Schlafen 11 (SLFN11) is an interferon-inducible antiviral restriction factor with tRNA endoribonuclease and DNA binding functions. It is recruited to stalled replication forks in response to replication stress and inhibits replication of certain viruses such as the human immunodeficiency virus 1 (HIV-1) by modulating the tRNA pool. SLFN11 has been identified as a predictive biomarker in cancer, as its expression correlates with a beneficial response to DNA damage inducing anticancer drugs. However, the mechanism and interdependence of these two functions are largely unknown. Here, we present cryo-electron microscopy (cryo-EM) structures of human SLFN11 in its dimeric apoenzyme state, bound to tRNA and in complex with single-strand DNA. Full-length SLFN11 neither hydrolyses nor binds ATP and the helicase domain appears in an autoinhibited state. Together with biochemical and structure guided mutagenesis studies, our data give detailed insights into the mechanism of endoribonuclease activity as well as suggestions on how SLFN11 may block stressed replication forks.
    DOI:  https://doi.org/10.1038/s41467-022-33123-0
  43. Nat Commun. 2022 Sep 23. 13(1): 5597
    Transition metal dichalcogenide metaphotonic and self-coupled polaritonic platform grown by chemical vapor deposition.
    Fuhuan Shen, Zhenghe Zhang, Yaoqiang Zhou, Jingwen Ma, Kun Chen, Huanjun Chen, Shaojun Wang, Jianbin Xu, Zefeng Chen.
      Transition metal dichalcogenides (TMDCs) have recently attracted growing attention in the fields of dielectric nanophotonics because of their high refractive index and excitonic resonances. Despite the recent realizations of Mie resonances by patterning exfoliated TMDC flakes, it is still challenging to achieve large-scale TMDC-based photonic structures with a controllable thickness. Here, we report a bulk MoS2 metaphotonic platform realized by a chemical vapor deposition (CVD) bottom-up method, supporting both pronounced dielectric optical modes and self-coupled polaritons. Magnetic surface lattice resonances (M-SLRs) and their energy-momentum dispersions are demonstrated in 1D MoS2 gratings. Anticrossing behaviors with Rabi splitting up to 170 meV are observed when the M-SLRs are hybridized with the excitons in multilayer MoS2. In addition, distinct Mie modes and anapole-exciton polaritons are also experimentally demonstrated in 2D MoS2 disk arrays. We believe that the CVD bottom-up method would open up many possibilities to achieve large-scale TMDC-based photonic devices and enrich the toolbox of engineering exciton-photon interactions in TMDCs.
    DOI:  https://doi.org/10.1038/s41467-022-33088-0
  44. EMBO Rep. 2022 Sep 23. e54507
    Ca2+ -independent transmission at the central synapse formed between dorsal root ganglion and dorsal horn neurons.
    Yuan Wang, Rong Huang, Zuying Chai, Changhe Wang, Xingyu Du, Yuqi Hang, Yongxin Xu, Jie Li, Xiaohan Jiang, Xi Wu, Zhongjun Qiao, Yinglin Li, Bing Liu, Xianying Zhang, Peng Cao, Feipeng Zhu, Zhuan Zhou.
      A central principle of synaptic transmission is that action potential-induced presynaptic neurotransmitter release occurs exclusively via Ca2+ -dependent secretion (CDS). The discovery and mechanistic investigations of Ca2+ -independent but voltage-dependent secretion (CiVDS) have demonstrated that the action potential per se is sufficient to trigger neurotransmission in the somata of primary sensory and sympathetic neurons in mammals. One key question remains, however, whether CiVDS contributes to central synaptic transmission. Here, we report, in the central transmission from presynaptic (dorsal root ganglion) to postsynaptic (spinal dorsal horn) neurons in vitro, (i) excitatory postsynaptic currents (EPSCs) are mediated by glutamate transmission through both CiVDS (up to 87%) and CDS; (ii) CiVDS-mediated EPSCs are independent of extracellular and intracellular Ca2+ ; (iii) CiVDS is faster than CDS in vesicle recycling with much less short-term depression; (iv) the fusion machinery of CiVDS includes Cav2.2 (voltage sensor) and SNARE (fusion pore). Together, an essential component of activity-induced EPSCs is mediated by CiVDS in a central synapse.
    Keywords:  Ca2+-dependent secretion; Ca2+-independent but voltage-dependent secretion; dorsal horn; dorsal root ganglion; synaptic transmission
    DOI:  https://doi.org/10.15252/embr.202154507
  45. Nat Aging. 2022 Jul;2(7): 601-615
    Characterization of cellular senescence in aging skeletal muscle.
    Xu Zhang, Leena Habiballa, Zaira Aversa, Yan Er Ng, Ayumi E Sakamoto, Davis A Englund, Vesselina M Pearsall, Thomas A White, Matthew M Robinson, Donato A Rivas, Surendra Dasari, Adam J Hruby, Anthony B Lagnado, Sarah K Jachim, Antoneta Granic, Avan A Sayer, Diana Jurk, Ian R Lanza, Sundeep Khosla, Roger A Fielding, K Sreekumaran Nair, Marissa J Schafer, João F Passos, Nathan K LeBrasseur.
      Senescence is a cell fate that contributes to multiple aging-related pathologies. Despite profound age-associated changes in skeletal muscle (SkM), whether its constituent cells are prone to senesce has not been methodically examined. Herein, using single cell and bulk RNA-sequencing and complementary imaging methods on SkM of young and old mice, we demonstrate that a subpopulation of old fibroadipogenic progenitors highly expresses p16 Ink4a together with multiple senescence-related genes and, concomitantly, exhibits DNA damage and chromatin reorganization. Through analysis of isolated myofibers, we also detail a senescence phenotype within a subset of old cells, governed instead by p2 Cip1 . Administration of a senotherapeutic intervention to old mice countered age-related molecular and morphological changes and improved SkM strength. Finally, we found that the senescence phenotype is conserved in SkM from older humans. Collectively, our data provide compelling evidence for cellular senescence as a hallmark and potentially tractable mediator of SkM aging.
    DOI:  https://doi.org/10.1038/s43587-022-00250-8
  46. J Exp Med. 2022 Dec 05. pii: e20220621. [Epub ahead of print]219(12):
    Impaired immune response drives age-dependent severity of COVID-19.
    Julius Beer, Stefania Crotta, Angele Breithaupt, Annette Ohnemus, Jan Becker, Benedikt Sachs, Lisa Kern, Miriam Llorian, Nadine Ebert, Fabien Labroussaa, Tran Thi Nhu Thao, Bettina Salome Trueeb, Joerg Jores, Volker Thiel, Martin Beer, Jonas Fuchs, Georg Kochs, Andreas Wack, Martin Schwemmle, Daniel Schnepf.
      Severity of COVID-19 shows an extraordinary correlation with increasing age. We generated a mouse model for severe COVID-19 and show that the age-dependent disease severity is caused by the disruption of a timely and well-coordinated innate and adaptive immune response due to impaired interferon (IFN) immunity. Aggravated disease in aged mice was characterized by a diminished IFN-γ response and excessive virus replication. Accordingly, adult IFN-γ receptor-deficient mice phenocopied the age-related disease severity, and supplementation of IFN-γ reversed the increased disease susceptibility of aged mice. Further, we show that therapeutic treatment with IFN-λ in adults and a combinatorial treatment with IFN-γ and IFN-λ in aged Ifnar1-/- mice was highly efficient in protecting against severe disease. Our findings provide an explanation for the age-dependent disease severity and clarify the nonredundant antiviral functions of type I, II, and III IFNs during SARS-CoV-2 infection in an age-dependent manner. Our data suggest that highly vulnerable individuals could benefit from immunotherapy combining IFN-γ and IFN-λ.
    DOI:  https://doi.org/10.1084/jem.20220621
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