Biology subjects

Lin, Q.

Publications and source records attributed to Lin, Q..

At least 73 records · Page 4Linked to original sources

bioRxiv2023

Single-cell RNA sequencing to explore the immune process difference between Kawasaki disease and febrile patients

BackgroundKawasaki disease (KD) is an acute systemic vasculitis that can lead to acquired heart disease in children mostly from in developed countries. The previous research showed that B cells in KD patients underwent a profound change in both the cell numbers and types after intravenous immunoglobulin (IVIG) therapy. MethodsWe performed the single-cell RNA-sequencing for the peripheral blood mononuclear cells (PBMCs) from three febrile patients and three KD patients to investigate the possible mechanism underlying B cell developmental dysfunction in KD. A previously published single-cell sequencing KD dataset (GSE168732) was also utilized in study for sample size expansion and validation. The comprehensive single-cell data analyses were applied for our dataset and GSE168732 dataset including single-cell trajectory analysis. To validate the immune disorders in KD, we measured immune-related indicators from 28 KD and 28 febrile patients. ResultOverall single-cell expression profiles show that the biological processes of immunity, B cell activation pathway and their related biological entities are repressed in KD patients before IVIG treatment compared to febrile patient and KD patients after IVIG treatment. The differentially expressed gene analyses further demonstrate that B cell signaling pathway is downregulated in B cells and plasma blast cells of KD patients before treatment while cell cycle genes and MYC gene are upregulated in dendritic cells (DCs) and hematopoietic stem and progenitor cells (HSPCs) of KD patients before treatment. The biological process of immune response is upregulated in the HSPCs of KD patients before treatment in our dataset while the biological process of inflammatory response is upregulated in the HSPCs of KD patients before treatment in GSE168732 dataset. Single-cell trajectory analyses demonstrate that KD patients before treatment have a shortened developmental path in which B cells and T cells are failed to differentiate into separate lineages. HSPD1 and HSPE1 genes show an elevated expression level in the early cell development stage of KD patients before treatment accompanied with the repression of MYC, SPI1, MT2A and UBE2C genes. Our analyses of all B cells from KD patients before treatment show most of B cells are arrested in a transitional state with an ill developmental path compared with febrile patients and KD patients after treatment. The percentage and absolute value of CD8 T cells in KD were lower than those in febrile patients. The ratio of CD4/CD8 in KD was higher than it in febrile patients. The serum levels of IgG and IgM in KD were lower than those in febrile patients. ConclusionsOur results indicate that the immune premature HSPCs accompanied with the abnormal expression dynamics of cell cycle and SPI1 genes are the mechanism underlying B cell developmental dysfunction in KD patients. FundingThis work is jointly supported by National Natural Science Foundation of China (82170518) and the Shanghai Science and Technology Committee research Funding (22Y11909700) and Shanghai Jinshan District medical key specialty Funding (JSZK2023A04).

immunology↗

bioRxiv2023

Single-cell transcriptomic analyses reveal the cellular and genetic basis of aquatic locomotion in scyphozoan jellyfish

The authors have withdrawn their manuscript because the authors need to re-organize the data and writing. More experimental evidence from whole-mount ISH assay and RNAi assays will be added to support the viewpoints. Therefore, the authors do not wish this work to be cited as reference for the project. If you have any questions, please contact the corresponding author.

ecology↗

bioRxiv2023

FarmGTEx TWAS-server: an interactive web server for customized TWAS analysis in both human and farm animals

Transcriptome-wide association study (TWAS) is a powerful strategy for elucidating the molecular mechanisms behind the genetic loci of complex phenotypes. However, TWAS analysis is still daunting in many species due to the complication of the TWAS analysis pipeline, including the construction of the gene expression reference panel, gene expression prediction, and the subsequent association analysis in the large cohorts of genome-wide association study (GWAS). Farm animals are major protein sources and biomedical models for humans. To facilitate the translation of genetic findings across species, here we provide an interactive and easy-to-use multi-species TWAS web server for the entire community, called the FarmGTEx TWAS-server (http://twas.farmgtex.org), which is based on the GTEx and FarmGTEx projects. It includes gene expression data from 49, 34, and 23 tissues in 838 humans, 5,457 pigs, and 4,889 cattle, representing 38,180, 21,037, and 17,942 distinct eGenes in prediction models for humans, pigs, and cattle, respectively. It allows users to conduct gene expression prediction for any individuals with genotypes, GWAS summary statistics imputation, customized TWAS, and popular downstream functional annotation. It also provides 479,203, 1,208, and 657 tissue-gene-trait association trios for the research community, representing 1,129 human traits, 41 cattle traits, and 11 pig traits. In summary, the FarmGTEx TWAS-server is a one-stop solution for performing TWAS analysis for researchers without programming skills in both human and farm animal research communities. It will be maintained and updated timely within the FarmGTEx project to facilitate gene mapping and phenotype prediction within and across species.

bioinformatics↗

bioRxiv2022

Prenatal maternal stress promotes neural stem cell proliferation in the ependymal-subventricular zone of adult male offspring

Perturbations during critical time windows during embryonic development can lead to adverse functional consequences that manifest later in life. Here, we report that prenatal maternal stress (PNS) during the peak of embryonic neurogenesis (E14-delivery) dramatically increased numbers of proliferating neural stem/progenitor cells (NSC/NPCs) in the ependymal-subventricular zone (E-SVZ) and neuroblasts (NBs) in the rostral migratory stream and newborn neurons in the olfactory bulb (OB) of male mouse offspring without causing significant cell death or a deficit in cell migration to the OB. Mechanistically, bulk and single-nucleus transcriptomic analyses showed that PNS affected gene regulatory networks controlling cell cycle progression and stem cell maintenance, maturation of neural circuits, and gliogenesis in prenatally stressed (STR) offspring. More specifically, we found that prenatal exposure to mild maternal restraint-stress sustained MAPK (ERK) activity in the E-SVZ and thus prolonged NSC/NPC/NB proliferation in stressed brains. Moreover, we found PNS disorganized the cytoarchitecture of the glomerular layer of the OB, which may directly relate to the deficit in discriminating different social orders in stressed offspring. Compared to STR males, their female littermates showed less change in the number of proliferating cells in the E-SVZ.

neuroscience↗

bioRxiv2022

Diversity and ecological function of urease-producing bacteria in the cultivation environment of Gracilariopsis lemaneiformis

Urease-producing bacteria (UPB) provide inorganic nitrogen for primary producers by hydrolysis of urea. They play an important role in marine nitrogen cycle. However, there is still incomplete understanding of UPB and their ecological functions in the cultivation environment of red macroalage Gracilariopsis lemaneiformis. This study comprehensively analyzed the diversity of culturable UPB and explored their effects on urea uptake by G. lemaneiformis. Total 34 isolates belonging to four main bacterial phyla i.e. Proteobacteria, Bacteroidetes, Firmicutes, and Actinobacteria were identified through 16S rRNA sequencing and were screened for UPB by urea agar chromogenic medium assay and ureC gene cloning. Our data revealed that only 8 strains were found containing urease. These all UPB exhibited different urease activities by Berthelot reaction colorimetry assay. Furthermore, UPB with highest urease activity was selected to use as co-culture with G. lemaneiformis to explore its role in terms of promotion or inhibition of nitrogen uptake by G. lemaneiformis. The results showed that the urea consumption in culture media and the total cellular nitrogen in G. lemaneiformis found increased significantly in the UPB-co culture group than control i.e. in the sterile group (p < 0.05). Similarity, isotopic assay revealed that {delta}15N contents of G. lemaneiformis was significant higher in the UPB-co culture than in the control where {delta}15N-urea was the only nitrogen source in the culture media, indicating the UPB helped G. lemaneiformis to absorb more nitrogen from urea. Moreover, the highest content of {delta}15N was found in G. lemaneiformis with epiphytic bacteria, as compared to sterilized (control) showing that epiphytic bacteria along with UPB have compound effects in helping G. lemaneiformis absorb more nitrogen in urea. Taken together, these results provide unique insight into the ecological role of UPB and suggest that urease from macroalgae environment-associated bacteria might be important player in the marine nitrogen cycling. ImportanceTo the best of our knowledge, this is the first study ever conducted to isolate the culturable UPB from the cultivation environment of G. lemaneiformis by urea agar chromogenic medium assay, and also evaluate the effects of UPB on urea utilization in G. lemaneiformis by stable isotopic tracer technique. This study provides a new insight into the mechanism of organic nitrogen uptake and utilization in G. lemaneiformis, and is of great significance for a better understanding of the ecological role of functional bacteria (e.g. urease-producing bacteria) in the marine nitrogen cycling.

microbiology↗

bioRxiv2022

Characterization of the mIF4G domains in the RNA surveillance protein Upf2

Thirty percent of all mutations causing human diseases generate mRNAs with premature termination codons (PTCs). Recognition and degradation of these PTC-containing mRNAs is carried out by the mechanism known as nonsense-mediated mRNA decay (NMD). Upf2 is a scaffold protein known to be a central component of the NMD surveillance pathway. It harbors three middle domain of eukaryotic initiation factor 4G (mIF4G) domains in its N-terminal potentially important in regulating the surveillance pathway. In this study, we defined regions within the mIF4G-1 and mIF4G-2 that are required for proper function of NMD and translation termination in Saccharomyces cerevisiae Upf2. In addition, we narrowed down the activity of these regions to an aspartic acid (D59) in mIF4G-1 which is important for NMD activity and translation termination accuracy. Taken together, these studies suggest that inherent charged residues within mIF4G-1 of Upf2 play a role in the regulation of the NMD surveillance mechanism in S. cerevisiae.

biochemistry↗

bioRxiv2022

Spatial transcriptomics of T and B cell receptors uncovers lymphocyte clonal dynamics in human tissue.

The spatial distribution of lymphocyte clones within tissues is critical to their development, selection, and expansion. We have developed Spatial Transcriptomics of VDJ sequences (Spatial VDJ), which maps immunoglobulin and TR antigen receptors in human tissue sections. Spatial VDJ captures lymphocyte clones matching canonical T, B, and plasma cell distributions in tissues and amplifies clonal sequences confirmed by orthogonal methods. We confirm spatial congruency between paired receptor chains, develop a computational framework to predict receptor pairs, and link the expansion of distinct B cell clones to different tumor-associated gene expression programs. Spatial VDJ delineates B cell clonal diversity, class switch recombination, and lineage trajectories within their spatial context. Taken together, Spatial VDJ captures lymphocyte spatial clonal architecture across tissues, which could have important therapeutic implications. One-Sentence SummarySpatial transcriptomics-based technology co-captures T and B cell receptors within their anatomical niche in human tissue.

immunology↗

bioRxiv2022

A compendium of genetic regulatory effects across pig tissues

The Farm animal Genotype-Tissue Expression (FarmGTEx, https://www.farmgtex.org/) project has been established to develop a comprehensive public resource of genetic regulatory variants in domestic animal species, which is essential for linking genetic polymorphisms to variation in phenotypes, helping fundamental biology discovery and exploitation in animal breeding and human biomedicine. Here we present results from the pilot phase of PigGTEx (http://piggtex.farmgtex.org/), where we processed 9,530 RNA-sequencing and 1,602 whole-genome sequencing samples from pigs. We build a pig genotype imputation panel, characterize the transcriptional landscape across over 100 tissues, and associate millions of genetic variants with five types of transcriptomic phenotypes in 34 tissues. We study interactions between genotype and breed/cell type, evaluate tissue specificity of regulatory effects, and elucidate the molecular mechanisms of their action using multi-omics data. Leveraging this resource, we decipher regulatory mechanisms underlying about 80% of the genetic associations for 207 pig complex phenotypes, and demonstrate the similarity of pigs to humans in gene expression and the genetic regulation behind complex phenotypes, corroborating the importance of pigs as a human biomedical model.

genomics↗

bioRxiv2022

7SK methylation Promotes Transcriptional Activity upon Growth Factor Stimulation

A fundamental facet of cell signaling is the conversion of extracellular signals into adaptive transcriptional responses. The role of RNA modifications in this process is poorly understood. The small nuclear RNA 7SK prevents transcription elongation by sequestering the complex CDK9/CCNT1 (P-TEFb). We discovered that METTL3 methylates 7SK. The m6A methylation of 7SK in turn promotes its binding to heterogeneous nuclear ribonucleoproteins (HNRNPs), with consequent release of the HEXIM1/P-TEFb complex - leading to the induction of growth factor-stimulated transcriptional responses. The methylation of 7SK relies on the activation of METTL3 via phosphorylation downstream of growth factors-signaling pathways such as the epidermal growth factor (EGF). Our findings establish a novel function for the m6A modification in converting growth-factor signaling events to a transcriptional elongation regulatory response via an RNA-methylation-dependent switch. One-Sentence Summarym6A methylation of the non-coding RNA 7SK promotes transcriptional activity upon growth factor stimulation.

molecular biology↗

bioRxiv2022

Entropic control of the free energy landscape of an archetypal biomolecular machine

Biomolecular machines are complex macromolecular assemblies that utilize thermal and chemical energy to perform essential, multistep, cellular processes. Despite possessing different architectures and functions, an essential feature of the mechanisms-of-action of all such machines is that they require dynamic rearrangements of structural components. Surprisingly, biomolecular machines generally possess only a limited set of such motions, suggesting that these dynamics must be repurposed to drive different mechanistic steps. Although ligands that interact with these machines are known to drive such repurposing, the physical and structural mechanisms through which ligands achieve this remain unknown. Using temperature-dependent, single-molecule measurements analyzed with a time-resolution-enhancing algorithm, here we dissect the free energy landscape of an archetypal biomolecular machine, the bacterial ribosome, to reveal how its dynamics are repurposed to drive distinct steps during ribosome-catalyzed protein synthesis. Specifically, we show that the free energy landscape of the ribosome encompasses a network of allosterically coupled structural elements that coordinates the motions of these elements. Moreover, we reveal that ribosomal ligands which participate in disparate steps of the protein synthesis pathway repurpose this network by differentially modulating the structural flexibility of the ribosomal complex (i.e., the entropic component of the free energy landscape). We propose that such ligand-dependent entropic control of free energy landscapes has evolved as a general strategy through which ligands may regulate the functions of all biomolecular machines. Such entropic control is therefore an important driver in the evolution of naturally occurring biomolecular machines and a critical consideration for the design of synthetic molecular machines.

biophysics↗

bioRxiv2022

Simultaneous and sequential multi-species coronavirus vaccination

Although successful COVID-19 vaccines have been developed, multiple pathogenic coronavirus species exist, urging for development of multi-species coronavirus vaccines. Here we developed prototype LNP-mRNA vaccine candidates against SARS-CoV-2 (Delta variant), SARS-CoV and MERS-CoV, and test how multiplexing of these LNP-mRNAs can induce effective immune responses in animal models. A triplex scheme of LNP-mRNA vaccination induced antigen-specific antibody responses against SARS-CoV-2, SARS-CoV and MERS-CoV, with a relatively weaker MERS-CoV response in this setting. Single cell RNA-seq profiled the global systemic immune repertoires and the respective transcriptome signatures of multiplexed vaccinated animals, which revealed a systemic increase in activated B cells, as well as differential gene expression signatures across major adaptive immune cells. Sequential vaccination showed potent antibody responses against all three species, significantly stronger than simultaneous vaccination in mixture. These data demonstrated the feasibility, antibody responses and single cell immune profiles of multi-species coronavirus vaccination. The direct comparison between simultaneous and sequential vaccination offers insights on optimization of vaccination schedules to provide broad and potent antibody immunity against three major pathogenic coronavirus species. One sentence summaryMultiplexed mRNA vaccination in simultaneous and sequential modes provide broad and potent immunity against pathogenic coronavirus species.

immunology↗

bioRxiv2022

Heterotypic vaccination responses against SARS-CoV-2 Omicron BA.2

The Omicron sub-lineage BA.2 of SARS-CoV-2 has recently become dominant across many areas in the world in the on-going waves of COVID-19. Compared to the ancestral/wild-type (WT) virus, Omicron lineage variants, both BA.1 and BA.2, contain high number of mutations, especially in the spike protein, causing significant immune escape that leads to substantial reduction of vaccine and antibody efficacy. Because of this antigenic drift, BA.2 exhibited differential resistance profile to monoclonal antibodies than BA.1. Thus, it is important to understand whether the immunity elicited by currently available vaccines are effective against the BA.2 subvariant. We directly tested the heterotypic vaccination responses against Omicron BA.2, using vaccinated serum from animals receiving WT- and variant-specific mRNA vaccine in lipid nanoparticle (LNP) formulations. Omicron BA.1 and BA.2 antigen showed similar reactivity to serum antibodies elicited by two doses of WT, B.1.351 and B.1.617 LNP-mRNAs. Neutralizing antibody titers of B.1.351 and B.1.617 LNP-mRNA were ~2-fold higher than that of WT LNP-mRNA. Both homologous boosting with WT LNP-mRNA and heterologous boosting with BA.1 LNP-mRNA substantially increased waning immunity of WT vaccinated mice against both BA.1 and BA.2 subvariants. The BA.1 LNP-mRNA booster was ~3-fold more efficient than WT LNP-mRNA at elevating neutralizing antibody titers of BA.2. Together, these data provided a direct preclinical evaluation of WT and variant-specific LNP-mRNAs in standard two-dose and as boosters against BA.1 and BA.2 subvariants.

immunology↗

bioRxiv2022

Potent and specific human monoclonal antibodies against SARS-CoV-2 Omicron variant by rapid mRNA immunization of humanized mice

The Omicron variant (B.1.1.529) of SARS-CoV-2 rapidly becomes dominant globally. Its extensive mutations confer severe efficacy reduction to most of existing antibodies or vaccines. Here, we developed RAMIHM, a highly efficient strategy to generate fully human monoclonal antibodies (mAbs), directly applied it with Omicron-mRNA immunization, and isolated three potent and specific clones against Omicron. Rapid mRNA immunization elicited strong anti-Omicron antibody response in humanized mice, along with broader anti-coronavirus activity. Customized single cell BCR sequencing mapped the clonal repertoires. Top-ranked clones collectively from peripheral blood, plasma B and memory B cell populations showed high rate of Omicron-specificity (93.3%) from RAMIHM-scBCRseq. Clone-screening identified three highly potent neutralizing antibodies that have low nanomolar affinity for Omicron RBD, and low ng/mL level IC50 in neutralization, more potent than majority of currently approved or authorized clinical RBD-targeting mAbs. These lead mAbs are fully human and ready for downstream IND-enabling and/or translational studies.

bioengineering↗

bioRxiv2022

The infiltration pattern of microenvironmental cells and different immune escape mechanisms in colorectal cancer

BackgroundThe tumour microenvironment (TME) plays a crucial role in tumour progression and metastasis. However, the infiltration pattern of TME cells in CRC samples and the immune escape mechanism underneath have not been studied sufficiently. MethodsTranscriptomic data from public datasets were retrieved online. In total, 1802 samples from the microarray dataset and 619 samples from the TCGA dataset were enrolled. The ssGSEA algorithm and unsupervised clustering were used for TME cells infiltration speculation and infiltration pattern recognition. ResultsCRC samples can be classified into three distinct TME cell subtypes. Subtype 1, the immune-active subtype, was characterised by high infiltration of activated adaptive immune cells. Subtype 2, the immune-desert subtype, featured high tumour purity and low infiltration of immune and stromal cells. And subtype 3, stroma-rich subtype, had high infiltration of stromal cells. The stroma-rich subtype conferred a significantly worse prognosis. Three subtypes had different immune escape mechanisms. The immune-active subtype has the highest immune checkpoint expression level. In comparison, the immune-desert subtype had the lowest immunogenicity and the defective antigen presentation. And the stroma-rich subtype lacked activated immune cells. ConclusionsDistinct TME cell subtypes and immune escape mechanisms may provide inspiration and direction for further researches on CRC immunotherapy.

cancer biology↗

bioRxiv2022

Comparative evaluation of glomerular morphometric techniques reveals differential technical artefacts between FSGS and normal glomeruli

Morphometric estimates of mean glomerular volume (MGV) have clinical implications, over and above histologic data. However, MGV estimation is time-consuming, could waste tissue sections and requires expertise limiting its utility in retrospective clinical studies. MethodsWe evaluated MGV using both plastic and paraffin-embedded tissue from control and FSGS mice (n=10 each) using the gold-standard Disector/Cavalieri technique (Vglom-Cav) and other reported techniques [2- or 3-profile technique, Weibel-Gomez method (W-G)]. Within Vglom-Cav we examined the precision of MGV estimation while using MGVs obtained from 5- or 10-individual glomeruli measurements vs the true mean (20 glomeruli). ResultsIn both FSGS and controls, we identified an acceptable precision of 10-glomerular sampling vs true MGV within Vglom-Cav technique [88 (79-94) % of MGV obtained were within 10% of the true MGV]. The 5-glomerular sampling was less precise [70 (56, 81) % of MGV obtained were within 10% of true MGV]. In plastic based techniques, 2- or 3-profile MGVs showed greater concordance with Vglom-Cav, than W-G MGV. The new 3-profile technique offered incremental benefit to the existing 2-profile method (improved Lins concordance in control and FSGS animals). We observed a consistent reduction of Vglom values within control animals (52+/-0.06%) in paraffin-embedded tissue (vs corresponding methods in plastic) demonstrating a clear shrinkage artefact due to tissue processing. FSGS glomeruli showed significantly less and more variable shrinkage artefact likely due to glomerular fibrosis. ConclusionWe report the precision of 5- or 10-glomerular sampling for MGV estimation using controls and FSGS animals. We demonstrate and quantify the shrinkage bias in MGV during tissue processing for paraffin-embedding that also differentiated control animals and FSGS. Our findings have implications for experimental studies using glomerular morphometry.

pathology↗

bioRxiv2022

SARS-CoV-2 Omicron-specific mRNA vaccine induces potent and broad antibody responses in vivo

The Omicron variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has high transmissibility and recently swept the globe. Due to the extensive number of mutations, this variant has high level of immune evasion, which drastically reduced the efficacy of existing antibodies and vaccines. Thus, it is important to test an Omicron-specific vaccine, evaluate its immune response against Omicron and other variants, and compare its immunogenicity as boosters with existing vaccine designed against the reference wildtype virus (WT). Here, we generated an Omicron-specific lipid nanoparticle (LNP) mRNA vaccine candidate, and tested its activity in animals, both alone and as a heterologous booster to existing WT mRNA vaccine. Our Omicron-specific LNP-mRNA vaccine elicited strong and specific antibody response in vaccination-naive mice. Mice that received two-dose WT LNP-mRNA, the one mimicking the commonly used Pfizer/Moderna mRNA vaccine, showed a >40-fold reduction in neutralization potency against Omicron variant than that against WT two weeks post second dose, which further reduced to background level >3 months post second dose. As a booster shot for two-dose WT mRNA vaccinated mice, a single dose of either a homologous booster with WT LNP-mRNA or a heterologous booster with Omicron LNP-mRNA restored the waning antibody response against Omicron, with over 40-fold increase at two weeks post injection as compared to right before booster. Interestingly, the heterologous Omicron LNP-mRNA booster elicited neutralizing titers 10-20 fold higher than the homologous WT booster against the Omicron variant, with comparable titers against the Delta variant. All three types of vaccination, including Omicron mRNA alone, WT mRNA homologous booster, and Omicron heterologous booster, elicited broad binding antibody responses against SARS-CoV-2 WA-1, Beta, and Delta variants, as well as other Betacoronavirus species such as SARS-CoV, but not Middle East respiratory syndrome coronavirus (MERS-CoV). These data provided direct proof-of-concept assessments of an Omicron-specific mRNA vaccination in vivo, both alone and as a heterologous booster to the existing widely-used WT mRNA vaccine form.

immunology↗

bioRxiv2022

Analysis of secondary metabolite gene clusters and chitin biosynthesis pathways of Monascus purpureus with high production of pigment and citrinin based on whole-genome sequencing

Monascus is a filamentous fungus that is commonly used for producing Monascus pigments in the food industry in Southeast Asia. While the development of bioinformatics has helped elucidate the molecular mechanism underlying secondary metabolite biosynthesis of Monascus, the biological information on the metabolic engineering of Monascus morphology remains unclear. In this study, we sequenced the whole genome of Monascus purpureus CSU-M183 strain by using combined single-molecule real-time DNA sequencing and next-generation sequencing platforms. The length of the genome assembly was 23.75 Mb in size with a GC content of 49.13% and 69 genomic contigs and encoded 7305 putative predicted genes. Furthermore, we identified secondary metabolite biosynthetic gene clusters and chitin synthesis pathways in the genome of the high pigment-producing M. purpureus CSU-M183 strain. And we confirmed that atmospheric room temperature plasma induced significant expression of the genes on Monascus pigments and citrinin biosynthetic gene cluster in M. purpureus CSU-M183 by RT-qPCR. These results provide a basis for understanding the secondary metabolite biosynthesis, the regulatory mechanisms of Monascus morphology, disrupting secondary metabolite biosynthesis in submerged fermentation, and the metabolic engineering of Monascus morphology.

microbiology↗

bioRxiv2022

ASGR1 is a candidate receptor for SARS-CoV-2 that promotes infection of liver cells

Backgroud & AimsCurrently, the COVID-19 pandemic, caused by SARS-CoV-2 infection, represents a serious public health problem worldwide. Although it has been shown that ACE2 serves as the main receptor for SARS-CoV-2 entry into host cells, studies have shown that ACE2 is expressed at extremely low levels in various tissues, especially in some organs where virus particles have been found, such as the heart and liver. Therefore, these organs potentially express additional SARS-CoV-2 receptors that have not yet been discovered. Methods & ResultsHere, by a genome-wide CRISPR-Cas9 activation library screening, we found that ASGR1 promoted SARS-CoV-2 infection of 293T cells. In Huh-7 and HepG2 cell lines, simultaneous knock out of ACE2 and ASGR1 prevented SARS-CoV-2 pseudovirus infection. In the immortalized THLE-2 hepatocyte cell line and primary liver parenchymal cells, both of which hardly express ACE2, SARS-CoV-2 could successfully establish an infection. After treatment with ASGR1 antibody, the infection rate significantly reduced. This suggests that SARS-CoV-2 infects liver cells mainly through an ASGR1-dependent mechanism. Finally, we also found that the soluble ASGR1 could not only prevent the SARS-CoV-2 pseudovirus, which binds to the ASGR1 receptors, from infecting host liver cells, but also had a protective effect on those expressing ACE2, indicating that administration of soluble ASGR1 protein may represent a new treatment approach. ConclusionsColletively, these findings indicate that ASGR1 is a candidate receptor for SARS-CoV-2 that promotes infection of liver cells. Lay SummaryWe show that ASGR1 is a candidate receptor for SARS-CoV-2 to infect liver cells.

microbiology↗