"Molecular Masks" for ACE2 to Effectively and Safely Block SARS-CoV-2 Virus Entry.
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ABSTRACT:
SUBMITTER: Shukla SP
PROVIDER: S-EPMC8396575 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Airborne transmission by droplets and aerosols is important for the spread of viruses. Face masks are a well-established preventive measure, but their effectiveness for mitigating SARS-CoV-2 transmission is still under debate. We show that variations in mask efficacy can be explained by different regimes of virus abundance and related to population-average infection probability and reproduction number. For SARS-CoV-2, the viral load of infectious individuals can vary by orders of magnitude. We find that most environments and contacts are under conditions of low virus abundance (virus-limited) where surgical masks are effective at preventing virus spread. More advanced masks and other protective equipment are required in potentially virus-rich indoor environments including medical centers and hospitals. Masks are particularly effective in combination with other preventive measures like ventilation and distancing.
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Project description:The current COVID-19 pandemic is causing profound health, economic, and social problems worldwide. The global shortage of medical and personal protective equipment (PPE) in specialized centers during the outbreak demonstrated the need for efficient methods to disinfect and recycle them in times of emergency. We have previously described that high ozone concentrations destroyed viral RNA in an inactivated SARS-CoV-2 strain within a few minutes. However, the efficient ozone dosages for active SARS-CoV-2 are still unknown. The present study aimed to evaluate the systematic effects of ozone exposure on face masks from hospitalized patients infected with SARS-CoV-2. Face masks from COVID-19 patients were collected and treated with a clinical ozone generator at high ozone concentrations in small volumes for short periods. The study focused on SARS-CoV-2 gene detection (assessed by real-time quantitative polymerase chain reaction (RT-qPCR)) and on the virus inactivation by in vitro studies. We assessed the effects of different high ozone concentrations and exposure times on decontamination efficiency. We showed that high ozone concentrations (10,000, 2,000, and 4,000 ppm) and short exposure times (10, 10, and 2 minutes, respectively), inactivated both the original strain and the B.1.1.7 strain of SARS-CoV-2 from 24 contaminated face masks from COVID-19 patients. The validation results showed that the best condition for SARS-CoV-2 inactivation was a treatment of 4,000 ppm of ozone for 2 minutes. Further studies are in progress to advance the potential applications of these findings.
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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.
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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.
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Project description:The frequently emerging SARS-CoV-2 variants have weakened the effectiveness of existing COVID-19 vaccines and neutralizing antibody therapy. Nevertheless, the infections of SARS-CoV-2 variants still depend on angiotensin-converting enzyme 2 (ACE2) receptor-mediated cell entry, and thus the soluble human ACE2 (shACE2) is a potential decoy for broadly blocking SARS-CoV-2 variants. In this study, we firstly generated the recombinant AAVrh10-vectored shACE2 constructs, a kind of adeno-associated virus (AAV) serotype with pulmonary tissue tropism, and then validated its inhibition capacity against SARS-CoV-2 infection. To further optimize the minimized ACE2 functional domain candidates, a comprehensive analysis was performed to clarify the interactions between the ACE2 orthologs from various species and the receptor binding domain (RBD) of SARS-CoV-2 spike (S) protein. Based on the key interface amino acids, we designed a series of truncated ACE2 orthologs, and then assessed their potential affinity to bind to SARS-CoV-2 variants RBD in silico. Of note, we found that the 24-83aa fragment of dog ACE2 (dACE224-83) had a higher affinity to the RBD of SARS-CoV-2 variants than that of human ACE2. Importantly, AAVrh10-vectored shACE2 or dACE224-83 constructs exhibited a broadly blockage breadth against SARS-CoV-2 prototype and variants in vitro and ex vivo. Collectively, these data highlighted a promising therapeutic strategy against SARS-CoV-2 variants.
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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.
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