Biology subjects

Liang, Y.

Publications and source records attributed to Liang, Y..

At least 253 records · Page 14Linked to original sources

bioRxiv2022

Imputing the parental origin of the sibling's haplotype from parental phenotypes

To recruit cases for late-onset disease study is challenging since these diseases occur in elder people. Moreover, typically we have a very limited number of late-onset disease cases in Biobank data. But, on the other hand, the parental disease status may be available by questionnaire. Because of this, methods have been developed to utilize parental disease status instead Liu et al. (2017); Hujoel et al. (2020). In these approaches, the late-onset phenotype of the participant is imputed from parental statuses. And, downstream, a genome-wide association study (GWAS) is performed using the participants genotype and imputed phenotype. In this paper, we take another view on utilizing parental phenotypes. We treat this problem as missing parental genotype rather than missing participants phenotype. First, we propose an imputation scheme to infer the parental origin of the participants genotype from a collection of extra parental phenotypes (non-focal phenotypes) and the participants genotype. Second, we propose a computationally efficient approach to incorporate the imputed parental origin information into the downstream GWAS. We explore the feasibility of the proposed two-step approach on simulated and real data. And we derive the power increase of GWAS as a function of imputation quality. These results indicate that the imputation scheme needs about 100 non-focal phenotypes to achieve enough accuracy to facilitate the GWAS downstream.

genetics↗

bioRxiv2022

Obtaining polygenic transcriptome risk scores (PTRS) directly from GWAS summary statistics

Polygenic Transcriptome Risk Scores (PTRS) are variations of Polygenic Risk Scores (PRS) that use genetically predicted transcriptome as features for prediction instead of directly using genetic variants. We have shown that when PTRS is combined with PRS, they can yield improved prediction performance and portability across populations (Liang et al., 2022). Given the difficulty of training PTRS using large scale individual-level data (due to both computational burden and the lack of data access), we developed a user friendly software that infers PTRS using GWAS summary results and reference LD. We tested three summary statistics-based PTRS approaches: i) Clumping and thresholding (clump-PTRS), keeping trait associated genes while removing highly correlated ones; ii) Summary statistics-based elastic net PTRS (S-EN-PTRS), an extension of lassosum (Mak et al., 2017) to predicted transcriptome; iii) Naive-PTRS, the sum of predicted expressions of significantly associated genes weighted by PrediXcan-estimated effect sizes (Gamazon et al., 2015). Despite reports that individual-level trained elastic net PTRS outperformed clump-PTRS in (Liang et al., 2022), for most of the 11 traits used in the comparison, clump-PTRS outperformed S-EN-PTRS, which outperformed naive-PTRS.

genetics↗

bioRxiv2022

Metformin protects trabecular meshwork against oxidative injury via activating integrin/ROCK signals

BackgroundThis study aimed to investigate the protective effect of metformin on the trabecular meshwork (TM) and explore its molecular mechanisms in vivo and in vitro. MethodsOcular hypertension (OHT) mouse models were induced with dexamethasone (DEX) and further treated with metformin to determine its IOP lowering effect. Cultured human TM cells (HTMC) were pre-stimulated with tert-butyl hydroperoxide (tBHP) to induce oxidative damage and then supplemented with metformin for another 24 h. The expression of fibrotic markers and integrin/ROCK signals, including -SMA, TGF-{beta}, fibronectin, F-actin, integrin beta 1, Rho-associated kinase (ROCK)1/2, AMP-activated protein kinase (AMPK), myosin light chain 1 (MLC 1), and F-actin were determined by western blotting (WB) and immunofluorescence (IF). Reactive oxygen species (ROS) content was analysed using flow cytometry (FCM). ResultsAdministration of metformin reduced the elevated IOP and alleviated the fibrotic activity of aqueous humour outflow in OHT models. Additionally, metformin rearranged the disordered cytoskeleton in the TM both in vivo and in vitro. Furthermore, metformin significantly inhibited ROS production and activated integrin/ROCK signalling induced by tBHP in HTMC. ConclusionMetformin reduced the elevated IOP in steroid-induced OHT mouse models and exerted its protective effects against oxidative injury by regulating cytoskeleton remodelling through the integrin/ROCK pathway. This study provides new insights into metformin use and preclinical evidence for the potential treatment of primary open-angle glaucoma.

pharmacology and toxicology↗

bioRxiv2022

Polygenic Transcriptome Risk Scores Can Translate Genetic Results Between Species

Genome-wide association studies (GWAS) have implicated specific alleles and genes as risk factors for numerous complex traits. However, translating GWAS results into biologically and therapeutically meaningful discoveries remains extremely challenging. Most GWAS results identify noncoding regions of the genome, suggesting that differences in gene regulation are the major driver of trait variability. To better integrate GWAS results with gene regulatory polymorphisms, we previously developed PrediXcan (also known as "transcriptome-wide association studies" or TWAS), which maps SNPs to predicted gene expression using GWAS data. In this study, we developed RatXcan, a framework that extends this methodology to outbred heterogeneous stock (HS) rats. RatXcan accounts for the close familial relationships among HS rats by modeling the relatedness with a random effect that encodes the genetic relatedness. RatXcan also corrects for polygenic-driven inflation because of the equivalence between a relatedness random effect and the infinitesimal polygenic model. To develop RatXcan, we trained transcript predictors for 8,934 genes using reference genotype and expression data from five rat brain regions. We found that the cis genetic architecture of gene expression in both rats and humans was sparse and similar across brain tissues. We tested the association between predicted expression in rats and two example traits (body length and BMI) using phenotype and genotype data from 5,401 densely genotyped HS rats and identified a significant enrichment between the genes associated with rat and human body length and BMI. Thus, RatXcan represents a valuable tool for identifying the relationship between gene expression and phenotypes across species and paves the way to explore shared biological mechanisms of complex traits. Author SummaryUnderstanding how genetic variation affects phenotypic variation is critical to leveraging the wealth of genetic studies to make biologically and therapeutically useful discoveries. Since most of the genetic loci associated with complex diseases are regulatory in nature--meaning that they do not alter protein coding but rather subtly affect gene expression--transcriptome-wide association studies have been developed. However, these apply only to human data where large samples of unrelated individuals are available. For animal models, relatedness is much higher, causing higher false-positive rates. We propose a computationally efficient method to address this problem and find shared biology between humans and rats. Taken together, our development paves the way to further explore shared biological mechanisms of complex traits across species.

genomics↗

bioRxiv2022

CD133+ Intercellsome Mediates Direct Cell-Cell Communication to Offset Intracellular Signaling Deficit

CD133 (prominin 1) is widely viewed as a cancer stem cell marker in association with drug resistance and cancer recurrence. Herein we report that with impaired RTK-Shp2 Ras-Erk signaling, heterogenous hepatocytes form clusters that manage to divide during liver regeneration. These hepatocytes are characterized by upregulated CD133 while negative for other progenitor cell markers. Pharmaceutical inhibition of proliferative signaling also induced CD133 expression in various cancer cell types, suggesting an inherent and common mechanism of stress response. Super-resolution and electron microscopy localize CD133 on intracellular vesicles that apparently migrate between cells, which we name "intercellsome". Isolated CD133+ intercellsomes are enriched with mRNAs rather than miRNAs. Single-cell RNA sequencing reveals lower intracellular diversity (entropy) of mitogenic mRNAs in Shp2-deficient cells, which may be remedied by intercellular mRNA exchanges between CD133+ cells. CD133-deficient cells are more sensitive to proliferative signal inhibition in livers and intestinal organoids. These data suggest a mechanism of intercellular communication to compensate intracellular signal deficit in various cell types.

cell biology↗

bioRxiv2022

CvkR, a novel MerR-type transcriptional regulator, is a repressor of class 2 type V-K CRISPR-associated transposase systems

CRISPR-associated transposons (CASTs) exist in different groups of bacteria, including certain cyanobacteria, which contain type V-K CAST systems. These systems contain genes encoding Tn7-like transposase subunits and a divergent number of cargo genes. How the activity of these systems is controlled in situ has remained largely unknown but possibly regulatory genes within these elements are prime candidates. Deletion of the respective regulator gene alr3614 in the cyanobacterium Anabaena (Nostoc) sp. PCC 7120 led to the overexpression of CRISPR tracrRNA, precursor crRNAs and mRNAs encoding the Cas12k effector protein (all3613) and Tn7-like transposase subunits. Upon complementation, these same genes were repressed again. DNase I footprinting and electrophoretic mobility shift assays verified the direct interaction between Alr3614 and the promoter of cas12k and identified a widely conserved binding motif. Structural analysis of Alr3614 at 1.5 [A] resolution revealed that it belongs to the MerR-type transcription factor family but with distinct dimerization and effector-binding domains. This protein assembles into a homodimer interacting with DNA through its N-terminal winged helix-turn-helix (wHTH) domain and binds an effector molecule through a C-terminal -helical domain lacking a conserved cysteine. These results identify Alr3614 as a transcriptional repressor of the CAST system in Anabaena sp. PCC 7120. We suggest naming this family of repressors CvkR for Cas V-K repressors, which are at the core of a widely conserved regulatory mechanism that controls type V-K CAST systems.

microbiology↗

bioRxiv2022

Host transcriptomic profiling of CD-1 outbred mice with severe clinical outcomes following infection with Orientia tsutsugamushi

Orientia tsutsugamushi is an obligately intracellular bacterium with endothelial tropism and can cause mild to lethal scrub typhus in humans. No vaccine is available for this reemerging and severely neglected infection. Previous scrub typhus studies have utilized inbred mice, yet such models have intrinsic limitations. Thus, the development of suitable mouse models that better mimic human diseases is in great need for immunologic investigation and future vaccine studies. This study is aimed at establishing scrub typhus in outbred CD-1 mice and defining immune biomarkers related to disease severity. CD-1 mice received O. tsutsugamushi Karp strain via the i.v. route; major organs were harvested at 2-12 days post-infection for kinetic analyses. We found that for our given infection doses, CD-1 mice were significantly more susceptible (90-100% lethal) than were inbred C57BL/6 mice (0-10% lethal). Gross pathology of infected CD-1 mouse organs revealed features that mimicked human scrub typhus, including pulmonary edema, interstitial pneumonia, perivascular lymphocytic infiltrates, and vasculitis. Alteration in angiopoietin/receptor expression in inflamed lungs implied endothelial dysfunction. Lung immune gene profiling using NanoString analysis displayed a Th1/CD8-skewed, but Th2 repressed profile, including novel biomarkers not previously investigated in other scrub typhus models. Bio-plex analysis revealed a robust inflammatory response in CD-1 mice as evidenced by increased serum cytokine and chemokine levels, correlating with immune cell recruitment during the severe stages of the disease. This study provides an important framework indicating a value of CD-1 mice for delineating host susceptibility to O. tsutsugamushi, immune dysregulation, and disease pathogenesis. This preclinical model is particularly useful for future translational and vaccine studies for severe scrub typhus. Author SummaryScrub typhus is a severely neglected and potentially fatal disease caused by Orientia tsutsugamushi, a genetically intractable, obligately intracellular bacterium that annually infects at least one million people worldwide. There is no vaccine available, and our current understanding of the host immunological response and mechanisms remains very limited. Appropriate animal models of infection that recapitulate the disease are essential to the development of effective therapeutics and vaccines. In this study, we characterized the immunologic responses by transcriptomics and Bio-plex assays in outbred CD-1 mice with lethal O. tsutsugamushi infection. We found that CD-1 mice were highly susceptible to infection and that the high mortality correlated with a Th1/CD8-skewed, but Th2 repressed, immune profile during the acute phase of disease. This proinflammatory state was further confirmed by elevated cytokine and chemokine levels in the sera. Collectively, this study established CD-1 mice as a practical, preclinical model to define pathogenic mechanisms underlying severe scrub typhus and for future immunologic and translational studies during O. tsutsugamushi infection.

microbiology↗

bioRxiv2022

Dynamic Landscapes of tRNA Transcriptomes and Translatomes in Diverse Mouse Tissues

Although the function of tRNA in translational process is well established, it remains controversial whether tRNA abundance is tightly associated with translational efficiency (TE) in mammals. For example, how critically the expression of tRNAs contributes to the establishment of tissue-specific proteomes in mammals has not been well addressed. Here, we measured both tRNA expression using DM-tRNA-seq and ribosome-associated mRNAs in the brain, heart, and testis of RiboTag mice. Remarkable variation in the expression of tRNA isodecoders was observed among the different tissues. When the statistical effect of isodecoder-grouping on reducing variations is considered through permutating the anticodons, we observed an expected reduction in the tissue-variations of anticodon expression, an unexpected smaller variation of anticodon usage bias, and an unexpected larger variation of tRNA isotype expression. Regardless whether or not they share the same anticodons, isotypes encoding the same amino acids are co-expressed across different tissues. Based on the tRNA expression and TE computed from RiboTag-seq, we find that the tRNA adaptation index (tAI) values and TE are significantly correlated in the same tissues but not among tissues; tRNAs and the amino acid compositions of translating peptides are positively correlated in the same tissues but not between tissues. We therefore hypothesize that the tissue-specific expression of tRNAs might be related to post-transcriptional mechanisms, such as aminoacylation, modification, and tRNA-derived small RNAs (tsRNAs). This study provides a resource for tRNA and translation studies to gain novel insights into the dynamics of tRNAs and their role in translational regulation.

cell biology↗

bioRxiv2022

An atlas of genetic scores to predict multi-omic traits

Genetically predicted levels of multi-omic traits can uncover the molecular underpinnings of common phenotypes in a highly efficient manner. Here, we utilised a large cohort (INTERVAL; N=50,000 participants) with extensive multi-omic data for plasma proteomics (SomaScan, N=3,175; Olink, N=4,822), plasma metabolomics (Metabolon HD4, N=8,153), serum metabolomics (Nightingale, N=37,359), and whole blood Illumina RNA sequencing (N=4,136). We used machine learning to train genetic scores for 17,227 molecular traits, including 10,521 which reached Bonferroni-adjusted significance. We evaluated genetic score performances in external validation across European, Asian and African American ancestries, and assessed their longitudinal stability within diverse individuals. We demonstrated the utility of these multi-omic genetic scores by quantifying the genetic control of biological pathways and by generating a synthetic multi-omic dataset of UK Biobank to identify disease associations using a phenome-wide scan. Finally, we developed a portal (OmicsPred.org) to facilitate public access to all genetic scores and validation results as well as to serve as a platform for future extensions and enhancements of multi-omic genetic scores.

genomics↗

bioRxiv2022

Maps of high density microsatellites accumulation in human genome

BackgroundMicrosatellites are increasingly realized to have biological significance in human genome and health in past decades, the assembled complete reference sequence of human genome T2T-CHM13 brought great help for a comprehensive study of short tandem repeats in the human genome. ResultsMicrosatellites density landscapes of all 24 chromosomes were built here for the first complete reference sequence of human genome T2T-CHM13. These landscapes showed that short tandem repeats (STRs) are prone to aggregate characteristically to form a large number of STRs density peaks. We classified 8,823 High Microsatellites Density Peaks (HMDPs), 35,257 Middle Microsatellites Density Peaks (MMDPs) and 199, 649 Low Microsatellites Density Peaks (LMDPs) on the 24 chromosomes; and also classified the motif types of every microsatellites density peak. These STRs density aggregation peaks are mainly composing of a single motif, and AT is the most dominant motif, followed by AATGG and CCATT motifs. And 514 genomic regions were characterized by microsatellite density feature in the full T2T-CHM13 genome. ConclusionsThese landscape maps exhibited that microsatellites aggregate in many genomic positions to form a large number of microsatellite density peaks with composing of mainly single motif type in the complete reference genome, indicating that the local microsatellites density varies enormously along the every chromosome of T2T-CHM13.

bioinformatics↗

bioRxiv2022

A mosaic-type trimeric RBD-based COVID-19 vaccine candidate induces potent neutralization against Omicron and other SARS-CoV-2 variants

Large-scale populations in the world have been vaccinated with COVID-19 vaccines, however, breakthrough infections of SARS-CoV-2 are still growing rapidly due to the emergence of immune-evasive variants, especially Omicron. It is urgent to develop effective broad-spectrum vaccines to better control the pandemic of these variants. Here, we present a mosaic-type trimeric form of spike receptor-binding domain (mos-tri-RBD) as a broad-spectrum vaccine candidate, which carries the key mutations from Omicron and other circulating variants. Tests in rats showed that the designed mos-tri-RBD, whether used alone or as a booster shot, elicited potent cross-neutralizing antibodies against not only Omicron but also other immune-evasive variants. Neutralizing antibody titers induced by mos-tri-RBD were substantially higher than those elicited by homo-tri-RBD (containing homologous RBDs from prototype strain) or the inactivated vaccine BBIBP-CorV. Our study indicates that mos-tri-RBD is highly immunogenic, which may serve as a broad-spectrum vaccine candidate in combating SARS-CoV-2 variants including Omicron.

immunology↗

bioRxiv2022

Tree species and genetic diversity increase productivity via functional diversity and trophic feedbacks

Addressing global biodiversity loss requires an expanded focus on multiple dimensions of biodiversity. While most studies have focused on the consequences of plant interspecific diversity, our mechanistic understanding of how the diversity within a given plant species (genetic diversity) affects plant productivity remains limited. Here, we use a tree species x genetic diversity experiment to disentangle the effects of species diversity and genetic diversity, and how they are related to tree functional diversity and trophic feedbacks. Tree species as well as genetic diversity increased tree productivity via increased tree functional diversity, reduced soil fungal diversity and marginally reduced herbivory. The effect of tree genetic diversity on productivity was partly different between tree species monocultures and mixtures: the functional diversity effect resulting from tree genetic diversity was only found in tree species monocultures, but the trophic feedbacks via herbivory were similar in species monocultures and mixtures. Given the complexity of interactions between tree species and genetic diversity, tree functional diversity and trophic feedbacks on productivity, we suggest that both tree species and genetic diversity should be considered in reforestation.

ecology↗

bioRxiv2022

Enzyme-Responsive Nanoparticles for the Targeted Delivery of an MMP Inhibitor to the Heart post Myocardial Infarction

In this paper, we describe block copolymer amphiphiles consisting of a hydrophilic matrix metalloproteinase (MMP) peptide substrate, and a hydrophobic small molecule MMP inhibitor PD166793 for the treatment of acute myocardial infarction. These resulting drug loaded peptide-polymer amphiphiles (PPAs) assemble in aqueous solution to yield drug loaded micellar nanoparticles. Following minimally invasive intravenous injection, these nanoparticles preferentially exit the vasculature and are physically trapped at the infarcted region of the heart due to MMP-induced peptide cleavage and aggregation. This MMP directed active assembly prevents the material from leaking out into the blood stream, enabling long-term retention. Further, we show that the conjugated MMP inhibitor (PD166793) is inactivated in the core of the micelles and can be released upon the action of proteases and esterases, leading to MMP inhibition. This work establishes a promising targeted nanoparticle platform for delivering small molecule therapeutics to the heart.

bioengineering↗

bioRxiv2022

Leishmania amazonensis infection induces PD-L1 expression on dendritic cells in an mTor-dependent manner and impairs Th1 responses in vitro and in vivo

Leishmania amazonensis is one of the etiological agents of diffuse cutaneous leishmaniasis in South America. In murine models of this infection, dysregulated expansion of effector T cells or exhaustion of Th1 responses are known to be related to pathogenesis, while the induction of regulatory T cells (Tregs) promotes lesion resolution. Recent research has identified several important co-stimulator/receptor pairs, including PD-1/PD-L1, for modulating Th1 responses and Treg induction. In this study, we examined the roles of these molecules in L. amazonensis-infected C57BL/6 mice. We found a significant and selective increase in the expression of PD-1 and PD-L1 (20-fold and 5-fold, respectively), in infected footpad tissues, which correlated with an increased percentage of PD-L1+CD11c+ dendritic cells (DCs) and PD-1+CD4+ T cells in the draining lymph nodes. To evaluate the mechanism of parasite-induced PD-L1 expression, we infected bone marrow-derived DCs (BMDCs) with promastigotes and amastigotes in vitro in the presence of small molecular inhibitors of critical signaling pathways. While L. amazonensis infection decreased PD-L2 expression on the surface of BMDCs, infection-mediated PD-L1 up-regulation was consistently detected, which was dependent on mTOR and partially dependent on STAT3, PI3K, and MAPK. Infected BMDCs also significantly inhibited the expansion of Th1 cells, but were more competent in inducing CD25+FoxP3+ Tregs in vitro than the non-infected BMDCs; such effects were PD-L1-dependent, as BMDCs from PD-L1-/- mice failed to do the same. In vivo experiments revealed that infected PD-L1-/- mouse tissues showed increased Th1 responses and IFN-{gamma} production, as well as reduced lesion sizes and parasite loads, without affecting Tregs cell expansion. Together, these results support a protective role for PD-1/PD-L1 signaling in regulating local immune responses during L. amazonensis infection. This study provides new insights on immune regulation in New World cutaneous leishmaniasis.

immunology↗

bioRxiv2022

A model of persistent post SARS-CoV-2 induced lung disease for target identification and testing of therapeutic strategies

COVID-19 survivors develop post-acute sequelae of SARS-CoV-2 (PASC), but the mechanistic basis of PASC-associated lung abnormalities suffers from a lack of longitudinal samples. Mouse-adapted SARS-CoV-2 MA10 produces an acute respiratory distress syndrome (ARDS) in mice similar to humans. To investigate PASC pathogenesis, studies of MA10-infected mice were extended from acute disease through clinical recovery. At 15-120 days post-virus clearance, histologic evaluation identified subpleural lesions containing collagen, proliferative fibroblasts, and chronic inflammation with tertiary lymphoid structures. Longitudinal spatial transcriptional profiling identified global reparative and fibrotic pathways dysregulated in diseased regions, similar to human COVID-19. Populations of alveolar intermediate cells, coupled with focal upregulation of pro-fibrotic markers, were identified in persistently diseased regions. Early intervention with antiviral EIDD-2801 reduced chronic disease, and early anti-fibrotic agent (nintedanib) intervention modified early disease severity. This murine model provides opportunities to identify pathways associated with persistent SARS-CoV-2 pulmonary disease and test countermeasures to ameliorate PASC.

microbiology↗

bioRxiv2022

Annelid functional genomics reveal the origins of bilaterian life cycles

Indirect development with an intermediate larva exists in all major animal lineages1, making larvae central to most scenarios of animal evolution2-12. Yet how larvae evolved remains disputed. Here we show that temporal shifts (i.e., heterochronies) in trunk formation underpin the diversification of larvae and bilaterian life cycles. Combining chromosome-scale genome sequencing in the slow-evolving annelid Owenia fusiformis13 with transcriptomic and epigenomic profiling during the life cycles of this and two other annelids, we found that trunk development is deferred to pre-metamorphic stages in the feeding larva of O. fusiformis, but starts after gastrulation in the non-feeding larva with gradual metamorphosis of Capitella teleta and the direct developing embryo of Dimorphilus gyrociliatus. Accordingly, the embryos of O. fusiformis develop first into an enlarged anterior domain that forms larval tissues and the adult head. Notably, this also occurs in the so-called "head larvae" of other bilaterians14,15, with whom O. fusiformis larva shows extensive transcriptomic similarities. Together, our findings suggest that the temporal decoupling of head and trunk formation, as maximally observed in "head larvae", allowed larval evolution in Bilateria, thus diverging from prevailing scenarios that propose either co-option10,11 or innovation12 of gene regulatory programmes to explain larva and adult origins.

genomics↗

bioRxiv2022

Genomic and phylogenetic analysis of the first myovirus isolated from Oceanospirillaceae, representing a novel viral cluster prevalent in polar oceans

The marine bacterial family Oceanospirillaceae, which is abundant in the deep-seas and polar oceans, is closely associated with algal blooms and petroleum hydrocarbons degradation. However, only a few Oceanospirillaceae-infecting phages have so far been reported. Here we report on a novel Oceanospirillum phage, vB_OsaM_PD0307, which is the first myovirus to be found that infects Oceanospirillaceae. vB_OsaM_PD0307 with a 44,421 bp linear dsDNA genome. Phylogenetic analysis and average nucleotide sequence identities suggest that vB_OsaM_PD0307 is different from other phage isolates and represents a novel genus-level myoviral cluster with two high-quality uncultured viral genomes, designed as Oceanospimyovirus. Additionally, the biogeographical distribution of the vB_OsaM_PD0307 cluster suggests that they are widespread in the oceans and abundant in polar areas. In summary, our findings expand the current understanding of the phylogenetic diversity, genomic characteristic and function of Oceanospimyovirus phages, and highlight the role of the vB_OsaM_PD0307 phage as a major ecological agent that can infect certain key bacterial groups associated with polar algal blooms. ImportanceOceanospirillumphage vB_OsaM_PD0307 is the first myovirus found to infect Oceanospirillaceae and represents a novel viral genus, Oceanospimyovirus. This study provides insights into the genomic, phylogenetic, and ecological characteristics of myoviruses infecting Oceanospirillaceae and improves our understanding of the interactions between Oceanospirillaceae and their phages in the oceans.

genomics↗

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↗