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Ren, Y.

Publications and source records attributed to Ren, Y..

At least 127 records · Page 7Linked to original sources
bioRxiv2023

Centrifuge+: improving metagenomic analysis upon Centrifuge

SummaryAccurate abundance estimation of species is essential for metagenomic analysis. Although many methods have been developed for classification of metagenomic data and abundance estimation of species, the abundance estimation of species remains challenging due to the ambiguous reads that align equally well to more than one genome. Here, we present Centrifuge+, which introduces unique mapping rate to describe the influence of similarities among species in the reference database when analyzing ambiguous reads. In contrast to the popular Centrifuge, Centrifuge+ improved the accuracy of abundance estimation on simulated reads from 4278 complete prokaryotic genomes. Availability and implementationThe source code is available at https://github.com/mNGSmethods/Centrifugep. Contacth.guo@foxmail.com or jlsljf0101@126.com Supplementary informationSupplementary data are available at Bioinformatics online.

bioinformatics↗
bioRxiv2023

A promising QTL QSns.sau-MC-3D.1 likely superior to WAPO1 for wheat spikelet number per spike shows no adverse effects on yield-related traits

Spikelet number per spike (SNS) is one of the crucial factors determining wheat yield. Thus, improving our understanding of the genes that regulate SNS could help develop higher-yielding wheat varieties. A genetic linkage map constructed using the GenoBaits Wheat 16K Panel and the 660K SNP array contained 5991 polymorphic SNP markers spanning 2813.26 cM. A total of twelve QTL for SNS were detected in the recombinant inbred line (RIL) population msf x Chuannong 16 (MC), and two of them, i.e., QSns.sau-MC-3D.1 and QSns.sau-MC-7A, were stably expressed. QSns.sau-MC-3D.1 had high LOD values ranging from 4.99 to 11.06 and explained 9.71-16.75% of the phenotypic variation. Comparison of QSns.sau-MC-3D.1 with previously reported SNS QTL suggested that it is likely a novel one. A kompetitive allele-specific PCR (KASP) marker, KASP-10, tightly linked to QSns.sau-MC-3D.1 was developed to successfully validate its effect in three segregated populations and a natural population. Genetic analysis indicated that WHEAT ORTHOLOG OFAPO1 (WAPO1) was a candidate gene for QSns.sau-MC-7A. The combined additive effect of QSns.sau-MC-3D.1 and WAP01 had a great additive effect increasing SNS by 7.10%. In addition, our results suggested that SNS is not affected by 1BL/1RS translocations in the MC RIL population. Correlation analysis between two major QTL and other agronomic traits showed that QSns.sau-MC-3D.1 was likely independent of these agronomic traits. However, the H2 haplotype of WAPO1 may affect effective tiller number and plant height. This indicated that the breeding potential of QSns.sau-MC-3D.1 is better than that of WAPO1. The geographical distribution of QSns.nsau-MC-3D.1 showed that QSns.sau-MC-3D.1 positive allele frequency was dominant in most wheat-producing regions of China and it has been positively selected among modern cultivars released in China since the 1940s. Two genes, TraesCS3D03G0222600 and TraesCS3D03G0216800, associated with SNS development were predicted in the physical interval of QSns.sau-MC-3D.1. qRT-PCR results of the two genes showed that only the expression level of TraesCS3D03G0216800 was significantly different between msf and CN16. These results enrich our understanding of the genetic basis of wheat SNS and will be useful for fine mapping and cloning of genes underlying QSns.sau-MC-3D.1, and provide a basis for marker-assisted selection breeding. Author summaryIn this study, we identified two major QTL (QSns.sau-MC-3D.1 and QSns.sau-MC-7A) in a RIL population. WAPO1 was demonstrated to be the candidate gene for QSns.sau-MC-7A. QSns.sau-MC-3D.1 was a novel and stably expressed QTL, and further confirmed in different genetic backgrounds. Our results further demonstrate that QSns.sau-MC-3D.1 has better breeding potential because of its no adverse effect on other agronomic traits than WAPO1, and it has been positively selected during Chinese breeding programs since the 1940s. Taken together, the identification of QSns.sau-MC-3D.1 offers a promising resource to further increase wheat yields.

genetics↗
bioRxiv2023

CRB3 navigates Rab11 trafficking vesicles to promote γTuRC assembly during ciliogenesis

The primary cilium plays important roles in regulating cell differentiation, signal transduction, and tissue organization. Dysfunction of the primary cilium can lead to ciliopathies and cancer. The formation and organization of the primary cilium are highly associated with cell polarity proteins, such as the apical polarity protein CRB3. However, the molecular mechanisms by which CRB3 regulates ciliogenesis and the location of CRB3 remain unknown. Here, we show that CRB3, as a navigator, regulates vesicle trafficking in {gamma}-TuRC assembly during ciliogenesis and cilium-related Hh and Wnt signaling pathways in tumorigenesis. Crb3 knockout mice display severe defects of the primary cilium in the mammary ductal lumen and renal tubule, while mammary epithelial-specific Crb3 knockout mice exhibit the promotion of ductal epithelial hyperplasia and tumorigenesis. CRB3 is essential for lumen formation and ciliary assembly in the mammary epithelium. We demonstrate that CRB3 localizes to the basal body and that CRB3 trafficking is mediated by Rab11-positive endosomes. Significantly, CRB3 interacts with Rab11 to navigate GCP6/Rab11 trafficking vesicles to CEP290, resulting in intact {gamma}-TuRC assembly. In addition, CRB3-depleted cells are unresponsive to the activation of the Hh signaling pathway, while CRB3 regulates the Wnt signaling pathway. Therefore, our studies reveal the molecular mechanisms by which CRB3 recognizes Rab11-positive endosomes to facilitate ciliogenesis, and regulates cilium-related signaling pathways in tumorigenesis.

cell biology↗
bioRxiv2023

A quantitative approach to measure and predict microbiome response to antibiotics

BackgroundAlthough antibiotics induce sizable perturbations in the human microbiome, we lack a systematic and quantitative method to measure and predict the microbiomes response to specific antibiotics. Here, we introduce such a method, which takes the form of a Microbiome Response Index (MiRIx) for each antibiotic. Antibiotic-specific MiRIx values quantify the overall susceptibility of the microbiota to an antibiotic, based on databases of bacterial phenotypes and published data on intrinsic antibiotic susceptibility. ResultsWe applied our approach to five published microbiome studies that carried out antibiotic interventions with vancomycin, metronidazole, ciprofloxacin, amoxicillin, and doxycycline. We show how MiRIx can be used in conjunction with existing microbiome analytical approaches to gain a deeper understanding of the microbiome response to antibiotics. Finally, we generate antibiotic response predictions for the oral, skin, and gut microbiome in healthy humans. ConclusionsOur approach is implemented as open-source software and is readily applied to microbiome data sets generated by 16S rRNA marker gene sequencing or shotgun metagenomics.

bioinformatics↗
bioRxiv2023

Identification of Immune-Related Candidate Biomarkers in Plasma of Patients with Sporadic Vestibular Schwannoma

Vestibular schwannoma (VS) is intracranial tumor arising from neoplastic Schwann cells, causing hearing loss in about 95% of patients. The traditional belief that hearing deficit is caused by physical expansion of the VS, compressing the auditory nerve, does not explain the common clinical finding that patients with small tumors can have profound hearing loss, suggesting that tumor-secreted factors could influence hearing ability in VS patients. Here, we conducted profiling of patients plasma for 67 immune-related factors on a large cohort of VS patients (N>120) and identified candidate biomarkers associated with tumor growth (IL-16 and S100B) and hearing (MDC). We identified the 7-biomarker panel composed of MCP-3, BLC, S100B, FGF-2, MMP-14, eotaxin, and TWEAK that showed outstanding discriminatory ability for VS. These findings revealed possible therapeutic targets for VS-induced hearing loss and provided a unique diagnostic tool that may predict hearing change and tumor growth in VS patients and may help inform the ideal timing of tumor resection to preserve hearing. TeaserProfiling of plasma in vestibular schwannoma patients revealed biomarkers that could predict hearing change and tumor growth.

neuroscience↗
bioRxiv2022

Integrated transcriptome and lineage analyses reveal novel catecholaminergic cardiomyocytes contributing to the cardiac conduction system in murine heart

Cardiac conduction system (CCS) morphogenesis is essential for correct heart function yet is incompletely understood. Here we established the transcriptional landscape of cell types populating the developing heart by integrating single-cell RNA sequencing and spatial enhanced resolution omics-sequencing (Stereo-seq). Stereo-seq provided a spatiotemporal transcriptomic cell fate map of the murine heart with a panoramic field of view and in situ cellular resolution of the CCS. This led to the identification of a previously unrecognized cardiomyocyte population expressing dopamine beta-hydroxylase (Dbh+-CMs), which is closely associated with the CCS in transcriptomic analyses. To confirm this finding, genetic fate mapping by using DbhCre/Rosa26-tdTomato reporter mouse line was performed with Stereo-seq, RNAscope, and immunohistology. We revealed that Dbh+-derived CMs first emerged in the sinus venosus at E12.5, then populated the atrial and ventricular CCS components at E14.5, with increasing abundance towards perinatal stages. Further tracing by using DbhCFP reporter and DbhCreERT/Rosa26-tdTomato inducible reporter, we confirmed that Dbh+-CMs are mostly abundant in the AVN and ventricular CCS and this persists in the adult heart. By using DbhCre/Rosa26-tdTomato/Cx40-eGFP compound reporter line, we validated a clear co-localization of tdTomato and eGFP signals in both left and right ventricular Purkinje fibre networks. Finally, electrophysiological optogenetic study using cell-type specific Channelrhodopsin2 (ChR2) expression further elucidated that Dbh+-derived CMs form a functional part of the ventricular CCS and display similar photostimulation-induced electrophysiological characteristics to Cx40CreERT/ChR2-tdTomato CCS components. Thus, by utilizing advanced transcriptomic, mouse genetic, and optogenetic functional analyses, our study provides new insights into mammalian CCS development and heterogeneity by revealing novel Dbh+-CMs. HighlightsO_LIStereo-seq provided a spatiotemporal transcriptomic cell fate map of the murine heart with a panoramic field of view and in situ cellular resolution of the CCS. C_LIO_LIEstablished the transcriptional landscape of cell types populating the developing murine heart. C_LIO_LIRevealed previously unreported catecholaminergic cardiomyocyte populations contributing to the developing and mature murine cardiac conduction system. C_LI

cell biology↗
bioRxiv2022

SurvivalML: an integrative platform for the discovery and exploration of prognostic models in multi-center cancer cohorts

Advances in multi-omics and big-data technologies have led to numerous prognostic signatures aimed at improving current clinicopathological staging systems. Due to the lack of reproducibility and independent confirmation, few signatures have been translated into clinical routine. As high-quality datasets accumulate, identifying robust signatures across multiple independent cohorts becomes possible. Nonetheless, inaccurate data retrieval, different versions of genome annotations, disparate expression distributions, difficult data cleaning, inconsistent clinical information, algorithm selection, and parameter tuning have impeded model development and validation in multi-center datasets. Hence, for the first time, we introduced SurvivalML (https://rookieutopia.com/app_direct/SurvivalML/), a web application for helping develop and validate prognostic models across multi-center datasets. SurvivalML included 37,325 samples (253 eligible datasets) with both transcriptome data and survival information from 21 cancer types, which were renewedly and uniformly re-annotated, normalized, and cleaned. This application provided 10 survival machine-learning algorithms for flexibly training models via tuning essential parameters online and delivered four aspects for model evaluation, including Kaplan-Meier survival analysis, time-dependent ROC, calibration curve, and decision curve analysis. Overall, we believe that SurvivalML can serve as an attractive platform for model discovery from multi-center datasets.

bioinformatics↗
bioRxiv2022

BEST: a web application for comprehensive biomarker exploration on large-scale data in solid tumors

SummaryData mining from RNA-seq or microarray data has become an essential part of cancer biomarker exploration. Certain existing web servers are valuable and broadly utilized, but the meta-analysis of multiple datasets is absent. Most web servers only contain tumor samples from the TCGA database with only one cohort for each cancer type, which also means that the analysis results mainly derived from a single cohort are thin and unstable. Indeed, consistent performance across multiple independent cohorts is the foundation for an excellent biomarker. Moreover, many analytical functions researchers require remain adequately unmet by these tools. Thus, we introduce BEST (Biomarker Exploration for Solid Tumors), a web application for comprehensive biomarker exploration on large-scale data in solid tumors. BEST includes more than 50,000 samples of 27 cancer types. To ensure the comparability of genes between different sequencing technologies and the legibility of clinical traits, we re-annotated transcriptome data based on the GRCh38 patch 13 sequences and unified the nomenclature of clinical traits. BEST delivers fast and customizable functions, including clinical association, survival analysis, enrichment analysis, cell infiltration, immunomodulator, immunotherapy, candidate agents, and genomic alteration. Together, our web server provides multiple cleaned-up independent datasets and diverse analysis functionalities, helping unleash the value of current data resources. It is freely available at https://rookieutopia.com/. The bigger pictureBioinformatics web servers enable researchers without computational programming skills to conduct various bioinformatics analyses. However, most web servers only contain tumor samples from the TCGA database with only one cohort for each cancer type, which also means that the analysis results mainly derived from a single cohort are thin and unstable. Thus, we introduce BEST (Biomarker Exploration for Solid Tumors), a web application for comprehensive biomarker exploration on large-scale data in solid tumors. BEST includes more than 50,000 samples of 27 cancer types that have been uniformly re-annotated based on the GRCh38 patch 13 sequences, which ensures the comparability of genes between different sequencing technologies. BEST also offers prevalent functions including clinical association, survival analysis, enrichment analysis, cell infiltration, immunomodulator, immunotherapy, candidate agents, and genomic alteration. Together, BEST provides a curated database and innovative analytical pipelines to explore cancer biomarkers at high resolution.

genomics↗
bioRxiv2022

The molecular mechanism of chloramphenicol and thiamphenicol resistance mediated by a novel oxidase CmO in Sphingomonadaceae

Antibiotic resistance mediated by bacterial enzyme inactivation plays a mysterious and crucial role for antibiotic degradation and selection pressure reduction in the environment. The enzymatic inactivation of the antibiotic chloramphenicol (CAP) involves nitro reduction, amide bond hydrolysis and acetylation modification. However, the molecular mechanism of enzymatic oxidation of CAP remains unknown. Here, a novel oxidase gene cmO was identified and confirmed biochemically to catalyze the resistance process through the oxidative inactivation at the side chain C-3 position of CAP and thiamphenicol (TAP) in Sphingomonadaceae. The oxidase CmO is highly conservative in Sphingomonadaceae and shares the highest amino acid homology of 41.05% with the biochemically identified glucose methanol choline (GMC) oxidoreductases. Molecular docking and site-directed mutagenesis analyses demonstrated that CAP was anchored inside the protein pocket of CmO with the hydrogen bonding of key residues glycine (G)99, asparagine (N)518, methionine (M)474 and tyrosine (Y)380. CAP sensitivity test demonstrated that the acetyltransferase and CmO showed higher resistance to CAP as compared with the amide bond-hydrolyzing esterase and nitroreductase. This study provides a better theoretical basis and a novel diagnostic gene for understanding and assessing the fate and resistance risk of CAP and TAP in the environment. ImportanceRising levels of antibiotic resistance undermines ecological and human health as a result of indiscriminate usage of antibiotics. Various resistance mechanisms have been revealed, for instance genes encoding proteins that degrade antibiotics, yet requiring further exploration. In this study, we reported a novel gene encoding an oxidase involved in the inactivation of typical amphenicol antibiotics (chloramphenicol and thiamphenicol), and the molecular mechanism was elucidated. The observation provides novel data to understand capabilities of bacteria to tackle antibiotic stress and suggests complex function of enzymes in the context of antibiotic resistance development and antibiotics removal. The reported gene can be further employed as an indicator to monitor amphenicols fate in the environment, benefiting the risk assessment in this era of antibiotic resistance.

microbiology↗
bioRxiv2022

Rnf20 shapes the endothelial control of heart morphogenesis and function

During embryogenesis, distinct cardiac cell types form, which shape the structural and functional properties of the heart. How their activity is coordinated is largely unknown. Here we show that Rnf20 is a multifaceted regulator of cardiac morphogenesis and function. On the one hand, Rnf20 controls extracellular matrix dynamics and endothelial-cardiomyocyte crosstalk essential for second heart field development. On the other hand, it safeguards endothelial cell identity and function by maintaining physiological angiocrine signaling and preventing endothelial-to-mesenchymal transition. Endothelial-specific deletion of Rnf20 led to ventricular septal defects, myocardial thinning and cardiac dysfunction as a result of aberrant signaling and excessive extracellular matrix deposition that induced precocious cardiomyocyte binucleation and irregular contractility. Furthermore, we uncovered upstream factors (e.g. Sox9) and multiple angiocrine and extracellular matrix molecules that alter cardiomyocyte functionality upon endothelial Rnf20 loss. In summary, our work identifies a novel, endothelial-specific role of Rnf20 in regulating cardiac morphogenesis and function.

developmental biology↗
bioRxiv2022

Endogenous Plasmids and Reductive Genome Evolution in Host-Associated Bacteria

Reductive genome evolution is commonly observed among host-associated bacteria including many important pathogens, such as Mycobacterium leprae but its molecular mechanism is not well understood 1-5. One of the most widely accepted hypotheses to explain bacterial genome reduction is Mullers ratchet, in which the associated bacteria tend to accumulate deleterious mutations for reduction in the absence of chromosomal recombination inside the eukaryotic host organism 1,2. Cardinium species belong to the family Amoebophilaceae of the CFB group bacteria, which are a group of endosymbiont bacteria widely distributed among arthropods, that along with Wolbachia can cause cytoplasmic incompatibility 6,7. In this study, we explored bacterial reductive evolution within the de novo assembled genomes of Cardinium endosymbionts in two astigmatic mites 8,9. Our results shed light on the reduction mechanism driven by endogenous plasmids and their encoded enzymes.

microbiology↗
bioRxiv2022

Gene interaction perturbation network deciphers a high-resolution taxonomy in colorectal cancer

Molecular subtypes of colorectal cancer (CRC) are currently identified via the snapshot transcriptional profiles, largely ignoring the dynamic changes of gene expressions. Conversely, biological networks remain relatively stable irrespective of time and condition. Here, we introduce an individual-specific gene interaction perturbation network-based (GIN) approach and identify six GIN subtypes (GINS1-6) with distinguishing features: (i) GINS1 (proliferative, 24%[~]34%), elevated proliferative activity, high tumor purity, immune-desert, PIK3CA mutations, and immunotherapeutic resistance; (ii) GINS2 (stromal-rich, 14%[~]22%), abundant fibroblasts, immune-suppressed, stem-cell-like, SMAD4 mutations, unfavorable prognosis, high potential of recurrence and metastasis, immunotherapeutic resistance, and sensitive to fluorouracil-based chemotherapy; (iii) GINS3 (KRAS-inactivated, 13%[~]20%), high tumor purity, immune-desert, activation of EGFR and ephrin receptors, chromosomal instability (CIN), fewer KRAS mutations, SMOC1 methylation, immunotherapeutic resistance, and sensitive to cetuximab and bevacizumab; (iv) GINS4 (mixed, 10%[~]19%), moderate level of stromal and immune activities, transit-amplifying-like, and TMEM106A methylation; (v) GINS5 (immune-activated, 12%[~]24%), stronger immune activation, plentiful tumor mutation and neoantigen burden, microsatellite instability and high CpG island methylator phenotype, BRAF mutations, favorable prognosis, and sensitive to immunotherapy and PARP inhibitors; (vi) GINS6, (metabolic, 5%[~]8%), accumulated fatty acids, enterocyte-like, and BMP activity. Overall, the novel high-resolution taxonomy derived from an interactome perspective could facilitate more effective management of CRC patients.

genetics↗
bioRxiv2022

Reducing chlorophyll level in seed filling stages results in higher seed nitrogen without impacting canopy carbon assimilation

Chlorophyll is the major light absorbing pigment for plant photosynthesis. While evolution has selected for higher chlorophyll content in leaves, previous work suggests that domesticated crops grown in modern agricultural environments overinvest in chlorophyll production thereby lowering light use and nitrogen use efficiency. To investigate the potential benefits of reducing chlorophyll level, we created ethanol inducible RNAi tobacco mutants that suppress Mg-chelatase subunit I (CHLI) with small RNA (sRNA) within 3 hours of induction and reduce chlorophyll within 5 days in field conditions. We initiated chlorophyll reduction later in plant development to avoid the highly sensitive seedling stage, and to allow young plants to have full green leaves to maximize light interception before canopy formation. This study demonstrated that >60% reduction of leaf chlorophyll could be tolerated without penalty on above-ground biomass or canopy photosynthesis in field conditions. Leaf chlorophyll reduction during seed filling stages increased tobacco seed nitrogen concentration as much as 17%, while biomass and seed yields were maintained. These results indicate that time-specific reduction of chlorophyll could be a niche strategy that decouples the inverse relationship between yield and seed nitrogen by utilizing saved nitrogen from the reduction of chlorophyll while maintaining full carbon assimilation capacity.

plant biology↗
bioRxiv2022

APOE deficiency impacts neural differentiation and cholesterol biosynthesis in human iPSC-derived cerebral organoids

The apolipoprotein E (APOE) gene is the strongest genetic risk factor for Alzheimers disease (AD); however, how it modulates brain homeostasis is not clear. The apoE protein is a major lipid carrier in the brain transporting lipids such as cholesterol among different brain cell types. Here, we show that APOE deficiency in human iPSC-derived cerebral organoids impacts brain lipid homeostasis by modulating multiple cellular and molecular pathways. Molecular profiling through single cell RNA-sequencing revealed that APOE deficiency leads to changes in cellular composition of isogenic cerebral organoids likely by modulating the EIF2 signaling pathway as these events were alleviated by the treatment of a pathway inhibitor ISRIB. APOE deletion also leads to activation of the Wnt/{beta}-catenin signaling pathway with concomitant decrease of SFRP1 expression in glia cells. Importantly, the critical role of apoE in cell type-specific lipid homeostasis was observed upon APOE deletion in cerebral organoids with a specific upregulation of cholesterol biosynthesis in excitatory neurons and excessive lipid accumulation in astrocytes. Relevant to human AD, APOE4 cerebral organoids show altered neurogenesis and cholesterol metabolism compared to those with APOE3. Our work demonstrates critical roles of apoE in brain homeostasis and offers critical insights into the APOE4-related pathogenic mechanisms.

cell biology↗
bioRxiv2022

Integrative signatures of signaling pathway response increase robustness and accuracy of pathway predictions

MotivationAberrant cell signaling is known to drive progression of cancer and many other diseases. The study of signaling pathways within cells is central to identifying drugs that seek to modulate these pathways. Expression of pathway genes (i.e. genes that code for pathway proteins) correlates poorly with signaling pathway activity, making prediction of signaling pathway activity changes based on transcriptional disease signatures a challenging problem. Pathway architecture and response also varies across cell lines, which reflects how drug response varies across a patient population. ResultsHere, we present a transcriptional footprinting framework for predicting changes in activity of signaling pathway by integrating transcriptional signatures of genetic perturbations of pathway genes over a diverse set of cell lines into a integrative Pathway Activity Signature (iPAS). We use an unsupervised multi-task learning approach to create pathway signatures across 12 cell lines using genetic loss of function data from the LINCS project. We also use supervised learning to construct an optimal predictor based on the ensemble of 12 cell line signatures. Our methods achieve a sizeable increase in performance, as measured by prediction of pathways targeted by LINCS chemical perturbagens. AvailabilityOpen source R package iPAS is available at https://github.com/uc-bd2k/iPAS. Contactmedvedm@ucmail.uc.edu Supplementary informationSupplementary data are available online.

bioinformatics↗
bioRxiv2022

Structure of nucleosome-bound human PBAF complex

BAF and PBAF are mammalian SWI/SNF family chromatin remodeling complexes that possess multiple histone/DNA-binding subunits and create nucleosome-depleted/free regions for transcription activation. Despite structural studies of nucleosome-bound human BAF and yeast SWI/SNF family complexes, it remains elusive how PBAF-nucleosome complex is organized. Here we determined structure of 13-subunit human PBAF in complex with acetylated nucleosome in ADP-BeF3-bound state. Four PBAF-specific subunits work together with nine BAF/PBAF-shared subunits to generate PBAF-specific modular organization, distinct from that of BAF at various regions. PBAF-nucleosome structure reveals six histone-binding domains and four DNA-binding domains/modules, the majority of which directly bind histone/DNA. This multivalent nucleosome-binding pattern, not observed in previous studies, suggests that PBAF may integrate comprehensive chromatin information to target genomic loci for function. Our study reveals molecular organization of subunits and histone/DNA-binding domains/modules in PBAF-nucleosome complex and provides a framework to understand chromatin targeting of SWI/SNF family complexes.

molecular biology↗
bioRxiv2022

Broadly neutralizing and protective nanobodies against diverse sarbecoviruses

As SARS-CoV-2 Omicron and other variants of concern continue spreading around the world, development of antibodies and vaccines to confer broad and protective activity is a global priority. Here, we report on the identification of a special group of nanobodies from immunized alpaca with exceptional breadth and potency against diverse sarbecoviruses including SARS-CoV-1, Omicron BA.1, and BA.2. Crystal structure analysis of one representative nanobody, 3-2A2-4, revealed a highly conserved epitope between the cryptic and the outer face of the receptor binding domain (RBD). The epitope is readily accessible regardless of RBD in "up" or "down" conformation and distinctive from the receptor ACE2 binding site. Passive delivery of 3-2A2-4 protected K18-hACE2 mice from infection of authentic SARS-CoV-2 Delta and Omicron. This group of nanobodies and the epitope identified should provide invaluable reference for the development of next generation antibody therapies and vaccines against wide varieties of SARS-CoV-2 infection and beyond.

immunology↗