Comparative analysis reveals the species-specific genetic determinants of ACE2 required for SARS-CoV-2 entry.
Ontology highlight
ABSTRACT:
SUBMITTER: Ren W
PROVIDER: S-EPMC7990223 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:SARS-CoV-2, the virus responsible for COVID-19, employs two key host proteins to gain entry and replicate within cells, angiotensin-converting enzyme 2 (ACE2) and the cell surface transmembrane protease serine 2 (TMPRSS2). TMPRSS2 was first characterized as an androgen-regulated gene in the prostate. Supporting a role for sex hormones, males relative to females are disproportionately affected by COVID-19 in terms of mortality and morbidity. Several studies, including one employing a large epidemiological cohort, suggested that blocking androgen signaling is protective against COVID-19. Here, we demonstrate that androgens regulate the expression of ACE2, TMPRSS2, and androgen receptor (AR) in subsets of lung epithelial cells. AR levels are markedly elevated in males relative to females greater than 70 years of age. In males greater than 70 years old, smoking was associated with elevated levels of AR and ACE2 in lung epithelial cells. Transcriptional repression of the AR enhancesome with AR or bromodomain and extraterminal domain (BET) antagonists inhibited SARS-CoV-2 infection in vitro. Taken together, these studies support further investigation of transcriptional inhibition of critical host factors in the treatment or prevention of COVID-19. These mouse data are part of a larger investigation (data not provided here) targeting the transcriptional regulation of SARS-CoV-2 entry factors ACE2 and TMPRSS2.
2020-11-30 | GSE159576 | GEO
Project description:BackgroundAngiotensin-converting enzyme 2 (ACE2) is known as the major viral entry site for SARS-CoV-2. However, viral tissue tropism and high rate of infectivity do not directly correspond with the level of ACE2 expression in the organs. It may suggest involvement of other receptors or accessory membrane proteins in SARSCoV-2 cell entry.Methods and resultsA systematic search was carried out in PubMed/Medline, EMBASE, and Cochrane Library for studies reporting SARS-CoV-2 cell entry. We used a group of the MeSH terms including "cell entry", "surface receptor", "ACE2", and "SARS-CoV-2". We reviewed all selected papers published in English up to end of February 2022. We found several receptors or auxiliary membrane proteins (including CD147, NRP-1, CD26, AGTR2, Band3, KREMEN1, ASGR1, ANP, TMEM30A, CLEC4G, and LDLRAD3) along with ACE2 that facilitate virus entry and transmission. Expression of Band3 protein on the surface of erythrocytes and evidence of binding with S protein of SARS-CoV-2 may explain asymptomatic hypoxemia during COVID19 infection. The variants of SARS-CoV-2 including the B.1.1.7 (Alpha), B.1.617.1 (Kappa), B.1.617.2 (Delta), B.1.617.2+ (Delta+), and B.1.1.529 (Omicron) may have different potency to bond with these receptors.ConclusionsThe high rate of infectivity of SARS-CoV-2 may be due to its ability to enter the host cell through a group of cell surface receptors. These receptors are potential targets to develop novel therapeutic agents for SARS-CoV-2.
| S-EPMC9244107 | biostudies-literature
Project description:Severe acute respiratory syndrome coronavirus (SARS-CoV) and SARS-CoV-2 have a single envelope glycoprotein (S protein) that binds to human angiotensin-converting enzyme 2 (ACE2) on the host cell membrane. Previous mutational scanning studies have suggested that some substitutions corresponding to single nucleotide variants (SNVs) in human ACE2 affect the binding affinity to the receptor binding domain (RBD) of the SARS-CoV-2 S protein. However, the importance of these substitutions in actual virus infection is still unclear. In this study, we investigated the effects of the reported ACE2 SNV substitutions on the entry of SARS-CoV and SARS-CoV-2 into cells, using vesicular stomatitis Indiana virus (VSIV) pseudotyped with S proteins of these coronaviruses (CoVs). HEK293T cells transfected with plasmids expressing ACE2 having each SNV substitution were infected with the pseudotyped VSIVs and relative infectivities were determined compared to the cells expressing wild-type ACE2. We found that some of the SNV substitutions positively or negatively affected the infectivities of the pseudotyped viruses. Particularly, the H505R substitution significantly enhanced the infection with the pseudotyped VSIVs, including those having the substitutions found in the S protein RBD of SARS-CoV-2 variants of concern. Our findings suggest that human ACE2 SNVs may potentially affect cell susceptibilities to SARS-CoV and SARS-CoV-2. IMPORTANCE SARS-CoV and SARS-CoV-2 are known to cause severe pneumonia in humans. The S protein of these CoVs binds to the ACE2 molecule on the plasma membrane and mediates virus entry into cells. The interaction between the S protein and ACE2 is thought to be important for host susceptibility to these CoVs. Although previous studies suggested that some SNV substitutions in ACE2 might affect the binding to the S protein, it remains elusive whether these SNV substitutions actually alter the efficiency of the entry of SARS CoVs into cells. We analyzed the impact of the ACE2 SNVs on the cellular entry of SARS CoVs using pseudotyped VSIVs having the S protein on the viral surface. We found that some of the SNV substitutions positively or negatively affected the infectivities of the viruses. Our data support the notion that genetic polymorphisms of ACE2 may potentially influence cell susceptibilities to SARS CoVs.
| S-EPMC9430119 | biostudies-literature
Project description:Despite the unprecedented effort of the scientific community, the novel SARS-CoV-2 virus has infected more than 46 million people worldwide, killing over one million two hundred thousand. Understanding the mechanisms by which some individuals are more susceptible to SARS-CoV-2 infection and why a subgroup of them are prone to experience severe pneumonia, and death should lead to a better approach and more effective treatments for COVID-19. Here, we focus our attention on ACE2, a primary receptor of SARS-CoV-2. We will discuss its biology, tissue expression, and post-translational regulation that determine its potential to be employed by SARS-CoV-2 for cell entry. Particular attention will be given to how the ACE2 soluble form can have a great impact on disease progression and thus be used in a potential therapeutic strategy. Furthermore, we will discuss repercussions that SARS-CoV-2/ACE2 binding has on the renin-angiotensin system and beyond. Indeed, although mostly neglected, ACE2 can also act on [des-Arg 937]-bradykinin of the kinin-kallikrein system regulating coagulation and inflammation. Thorough comprehension of the role that ACE2 plays in different pathways will be the key to assess the impact that SARS-CoV-2/ACE2 binding has on organismal physiology and will help us to find better therapies and diagnostic tools.
| S-EPMC7653219 | biostudies-literature
Project description:Integrins have been suggested to be involved in SARS-CoV-2 infection, but the underlying mechanisms remain largely unclear. This study aimed to investigate how integrins facilitate the ACE2-mediated cellular entry of SARS-CoV-2. We first tested the susceptibility of a panel of human cell lines to SARS-CoV-2 infection using the spike protein pseudotyped virus assay and examined the expression levels of integrins in these cell lines by qPCR, western blot and flow cytometry. We found that integrin αvβ1 was highly enriched in the SARS-CoV-2 susceptible cell lines. Additional studies demonstrated that RGD (403-405)→AAA mutant was defective in binding to integrin αvβ1 compared to its wild type counterpart, and anti-αvβ1 integrin antibodies significantly inhibited the entry of SARS-CoV-2 into the cells. Further studies using mouse NIH3T3 cells expressing human ACE2, integrin αv, integrin β1, and/or integrin αvβ1 suggest that integrin αvβ1 was unable to function as an independent receptor but could significantly facilitate the cellular entry of SASR-CoV-2. Finally, we observed that the Omicron exhibited a significant increase in the ACE2-mediated viral entry. Our findings may enhance our understanding of the pathogenesis of SARS-CoV-2 infection and offer potential therapeutic target for COVID-19.
| S-EPMC10651773 | biostudies-literature
Project description:The emergence of SARS-CoV-2 variants is a significant concern in developing effective therapeutics and vaccines in the middle of the ongoing COVID-19 pandemic. Here, we have identified a novel small molecule that inhibited the interactions between SARS-CoV-2 spike RBDs and ACE2 by modulating ACE2 without impairing its enzymatic activity necessary for normal physiological functions. Furthermore, the identified compounds suppressed viral infection in cultured cells by inhibiting the entry of ancestral and variant SARS-CoV-2. Our study suggests that targeting ACE2 could be a novel therapeutic strategy to inhibit SARS-CoV-2 entry into host cells and prevent the development of COVID-19.
| S-EPMC9011661 | biostudies-literature
Project description:The discovery of SARS-like coronavirus in bats suggests that bats could be the natural reservoir of SARS-CoV. However, previous studies indicated the angiotensin-converting enzyme 2 (ACE2) protein, a known SARS-CoV receptor, from a horseshoe bat was unable to act as a functional receptor for SARS-CoV. Here, we extended our previous study to ACE2 molecules from seven additional bat species and tested their interactions with human SARS-CoV spike protein using both HIV-based pseudotype and live SARS-CoV infection assays. The results show that ACE2s of Myotis daubentoni and Rhinolophus sinicus support viral entry mediated by the SARS-CoV S protein, albeit with different efficiency in comparison to that of the human ACE2. Further, the alteration of several key residues either decreased or enhanced bat ACE2 receptor efficiency, as predicted from a structural modeling study of the different bat ACE2 molecules. These data suggest that M. daubentoni and R. sinicus are likely to be susceptible to SARS-CoV and may be candidates as the natural host of the SARS-CoV progenitor viruses. Furthermore, our current study also demonstrates that the genetic diversity of ACE2 among bats is greater than that observed among known SARS-CoV susceptible mammals, highlighting the possibility that there are many more uncharacterized bat species that can act as a reservoir of SARS-CoV or its progenitor viruses. This calls for continuation and expansion of field surveillance studies among different bat populations to eventually identify the true natural reservoir of SARS-CoV.
| S-EPMC7086629 | biostudies-literature
Project description:The World Health Organization (WHO) declared coronavirus disease 2019 (COVID-19) as a public health emergency of international concern as more than 15 million cases were reported by 24th July 2020. Angiotensin-converting enzyme 2 (ACE2) is a COVID-19 entry receptor regulating host cell infection. A recent study reported that ACE2 is expressed in cardiomyocytes. In this study, we aimed to explore if there are microRNA (miRNA) molecules which target ACE2 and which may be exploited to regulate the SARS-CoV-2 receptor. Our data reveal that both Ace2 mRNA and Ace2 protein levels are inhibited by miR-200c in rat primary cardiomyocytes and importantly, in human iPSC-derived cardiomyocytes. We report the first miRNA candidate that can target ACE2 in cardiomyocytes and thus may be exploited as a preventive strategy to treat cardiovascular complications of COVID-19.
| S-EPMC7470794 | biostudies-literature
Project description:Since the beginning of the coronavirus disease 2019 (COVID-19) pandemic, much effort has been dedicated to identifying effective antivirals against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). A number of calpain inhibitors show excellent antiviral activities against SARS-CoV-2 by targeting the viral main protease (Mpro), which plays an essential role in processing viral polyproteins. In this study, we found that calpain inhibitors potently inhibited the infection of a chimeric vesicular stomatitis virus (VSV) encoding the SARS-CoV-2 spike protein but not Mpro. In contrast, calpain inhibitors did not exhibit antiviral activities toward the wild-type VSV with its native glycoprotein. Genetic knockout of calpain-2 by CRISPR/Cas9 conferred resistance of the host cells to the chimeric VSV-SARS-CoV-2 virus and a clinical isolate of wild-type SARS-CoV-2. Mechanistically, calpain-2 facilitates SARS-CoV-2 spike protein-mediated cell attachment by positively regulating the cell surface levels of ACE2. These results highlight an Mpro-independent pathway targeted by calpain inhibitors for efficient viral inhibition. We also identify calpain-2 as a novel host factor and a potential therapeutic target responsible for SARS-CoV-2 infection at the entry step.ImportanceMany efforts in small-molecule screens have been made to counter SARS-CoV-2 infection by targeting the viral main protease, the major element that processes viral proteins after translation. Here, we discovered that calpain inhibitors further block SARS-CoV-2 infection in a main protease-independent manner. We identified the host cysteine protease calpain-2 as an important positive regulator of the cell surface levels of SARS-CoV-2 cellular receptor ACE2 and, thus, a facilitator of viral infection. By either pharmacological inhibition or genetic knockout of calpain-2, the SARS-CoV-2 binding to host cells is blocked and viral infection is decreased. Our findings highlight a novel mechanism of ACE2 regulation, which presents a potential new therapeutic target. Since calpain inhibitors also potently interfere with the viral main protease, our data also provide a mechanistic understanding of the potential use of calpain inhibitors as dual inhibitors (entry and replication) in the clinical setting of COVID-19 diseases. Our findings bring mechanistic insights into the cellular process of SARS-CoV-2 entry and offer a novel explanation to the mechanism of activities of calpain inhibitors.
| S-EPMC10936414 | biostudies-literature
Project description:Coronavirus Disease 2019 (COVID-19) is a highly infectious and pathogenic disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Early in this epidemic, the herbal formulas used in traditional Chinese medicine (TCM) were widely used for the treatment of COVID-19 in China. According to Venn diagram analysis, we found that Glycyrrhizae Radix et Rhizoma is a frequent herb in TCM formulas against COVID-19. The extract of Glycyrrhizae Radix et Rhizoma exhibits an anti-SARS-CoV-2 replication activity in vitro, but its pharmacological mechanism remains unclear. We here demonstrate that glycyrrhizin, the main active ingredient of Glycyrrhizae Radix et Rhizoma, prevents the coronavirus from entering cells by targeting angiotensin-converting enzyme 2 (ACE2). Glycyrrhizin inhibited the binding of the spike protein of the SARS-CoV-2 to ACE2 in our Western blot-based assay. The following bulk RNA-seq analysis showed that glycyrrhizin down-regulated ACE2 expression in vitro which was further confirmed by Western blot and quantitative PCR. Together, we believe that glycyrrhizin inhibits SARS-CoV-2 entry into cells by targeting ACE2.
| S-EPMC9697465 | biostudies-literature