scholarly journals Basic Coronavirus biology and vaccines for COVID-19

2021 ◽  
Vol 39 (4) ◽  
Author(s):  
Hernan Garcia-Ruiz ◽  
Katherine LaTourrette ◽  
Mayra Teresa Garcia-Ruiz
Keyword(s):  
Middle East ◽  
Severe Acute Respiratory Syndrome ◽  
Diagnostic Test ◽  
Drug Administration ◽  
Diagnostic Tests ◽  
Protein S ◽  
Antiviral Drugs ◽  
Genomic Variation ◽  
Spike Protein ◽  
Human Coronaviruses

<p><em>Severe acute respiratory syndrome coronavirus 2</em> (SARS-CoV-2) is the causal agent of the COVID-19 pandemic. Two mRNA vaccines based on the spike protein S have been authorized by the Food and Drug Administration. Antibody-based diagnostic test detect antibodies developed against protein S. Mutations in the genome of SARS-CoV-2 might compromise the precision of diagnostic tests and the efficacy of vaccines and antiviral drugs. We recently profiled genomic variation in human coronaviruses SARS[1]CoV, SARS-CoV-2, and <em>Middle East respiratory syndrome coronavirus</em> (MERS-CoV). As in all species of the genus Betacoronavirus, the genome is hyper variable, and mutations are not random. The most variable cistron codes for the spike S protein. Hyper variation in protein S has the potential to affect the efficacy of vaccines, the reliability of antibody-based diagnostic test, and predicts potential for repeated SARS-CoV-2 infections. Here we review the basics of coronavirus biology and genomic variation, and link them to diagnostic tests, vaccines, and antiviral drugs.</p>

scholarly journals Epidemiological associations with genomic variation in SARS-CoV-2

2021 ◽  
Author(s):  
Ali Rahnavard ◽  
Rebecca Clement ◽  
Nathaniel Stearrett ◽  
Marcos Pérez-Losada ◽  
Keith A. Crandall ◽  
...  
Keyword(s):  
Severe Acute Respiratory Syndrome ◽  
Nonstructural Protein ◽  
Protein S ◽  
Disease Status ◽  
Virus Genome ◽  
Genomic Variation ◽  
Spike Protein ◽  
Genome Variation ◽  
Host Sex ◽  
Novel Coronavirus

Abstract The 2019 novel coronavirus (SARS-CoV-2) is the etiological agent of the COVID-19 pandemic and evolves to evade both host immune systems and intervention strategies. To diminish the short-term and long-term impacts of coronavirus (CoV), we investigated CoV differences at the nucleotide and protein level and CoV genomic variation associated with epidemiological variation and geography. We divided the CoV genome into 29 constituent regions for this analysis. Our results highlight the variation of CoV variants of lineage and show that nonstructural protein 3 (nsp3) and Spike protein (S) have the highest variation and greatest correlation with the viral whole-genome variation, which makes these two proteins potential targets for treatments. S protein variation is highly correlated with nsp3, nsp6, and 3'−to−5' exonuclease. Country of origin and time since the start of the pandemic were the most influential metadata in these differences. Host sex and age are the lowest in terms of explaining the virus genome variation. We quantified variation explained by regions of the CoV genome across different CoV viruses including, SARS-CoV-2, Middle East respiratory syndrome coronavirus (MERS-CoV), other severe acute respiratory syndrome coronavirus SARS-CoV (SARS-related), and bat-derived severe acute respiratory syndrome (SARS)-like coronaviruses (Bat-SL-CoV). We found that Spike protein and nsp3 explain most of the variation among these viruses; they are also among the genomic regions with the highest number of sites under natural selection. Our results provide a direction to prioritize genes associated with outcome predictors, including health, therapeutic, and vaccine outcomes, and to inform improved DNA tests for predicting disease status.

scholarly journals Immunological imprinting of the antibody response in COVID-19 patients

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Teresa Aydillo ◽  
Alexander Rombauts ◽  
Daniel Stadlbauer ◽  
Sadaf Aslam ◽  
Gabriela Abelenda-Alonso ◽  
...  
Keyword(s):  
Immune Response ◽  
Severe Acute Respiratory Syndrome ◽  
Antibody Response ◽  
Humoral Immune Response ◽  
Nucleocapsid Protein ◽  
Spike Protein ◽  
Ongoing Research ◽  
Variable Regions ◽  
Humoral Immune ◽  
Human Coronaviruses

AbstractIn addition to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), humans are also susceptible to six other coronaviruses, for which consecutive exposures to antigenically related and divergent seasonal coronaviruses are frequent. Despite the prevalence of COVID-19 pandemic and ongoing research, the nature of the antibody response against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is unclear. Here we longitudinally profile the early humoral immune response against SARS-CoV-2 in hospitalized coronavirus disease 2019 (COVID-19) patients and quantify levels of pre-existing immunity to OC43, HKU1 and 229E seasonal coronaviruses, and find a strong back-boosting effect to conserved but not variable regions of OC43 and HKU1 betacoronaviruses spike protein. However, such antibody memory boost to human coronaviruses negatively correlates with the induction of IgG and IgM against SARS-CoV-2 spike and nucleocapsid protein. Our findings thus provide evidence of immunological imprinting by previous seasonal coronavirus infections that can potentially modulate the antibody profile to SARS-CoV-2 infection.

scholarly journals Conformational States of the Severe Acute Respiratory Syndrome Coronavirus Spike Protein Ectodomain

2006 ◽  
Vol 80 (14) ◽  
pp. 6794-6800 ◽  
Author(s):  
Fang Li ◽  
Marcelo Berardi ◽  
Wenhui Li ◽  
Michael Farzan ◽  
Philip R. Dormitzer ◽  
...  
Keyword(s):  
Severe Acute Respiratory Syndrome ◽  
Membrane Fusion ◽  
Receptor Binding ◽  
Conformational Changes ◽  
Viral Entry ◽  
Protein S ◽  
Spike Protein ◽  
Fusion Peptides ◽  
Conformational States ◽  
Protease Cleavage

ABSTRACT The severe acute respiratory syndrome coronavirus enters cells through the activities of a spike protein (S) which has receptor-binding (S1) and membrane fusion (S2) regions. We have characterized four sequential states of a purified recombinant S ectodomain (S-e) comprising S1 and the ectodomain of S2. They are S-e monomers, uncleaved S-e trimers, cleaved S-e trimers, and dissociated S1 monomers and S2 trimer rosettes. Lowered pH induces an irreversible transition from flexible, L-shaped S-e monomers to clove-shaped trimers. Protease cleavage of the trimer occurs at the S1-S2 boundary; an ensuing S1 dissociation leads to a major rearrangement of the trimeric S2 and to formation of rosettes likely to represent clusters of elongated, postfusion trimers of S2 associated through their fusion peptides. The states and transitions of S suggest conformational changes that mediate viral entry into cells.

scholarly journals Binding and entering: COVID finds a new home

2021 ◽  
Vol 17 (8) ◽  
pp. e1009857
Author(s):  
Michelle N. Vu ◽  
Vineet D. Menachery
Keyword(s):  
Middle East ◽  
Severe Acute Respiratory Syndrome ◽  
Receptor Binding ◽  
Common Cold ◽  
Binding Domain ◽  
Middle East Respiratory Syndrome ◽  
Spike Protein ◽  
Receptor Binding Domain ◽  
Protease Cleavage ◽  
Pandemic Virus

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) emerged as a virus with a pathogenicity closer to Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV) and Middle East Respiratory Syndrome Coronavirus (MERS-CoV) and a transmissibility similar to common cold coronaviruses (CoVs). In this review, we briefly discuss the features of the receptor-binding domain (RBD) and protease cleavage of the SARS-CoV-2 spike protein that enable SARS-CoV-2 to be a pandemic virus.

scholarly journals Differential Downregulation of ACE2 by the Spike Proteins of Severe Acute Respiratory Syndrome Coronavirus and Human Coronavirus NL63

2009 ◽  
Vol 84 (2) ◽  
pp. 1198-1205 ◽  
Author(s):  
Ilona Glowacka ◽  
Stephanie Bertram ◽  
Petra Herzog ◽  
Susanne Pfefferle ◽  
Imke Steffen ◽  
...  
Keyword(s):  
Severe Acute Respiratory Syndrome ◽  
Lung Injury ◽  
Vero Cells ◽  
Cell Entry ◽  
Spike Protein ◽  
Converting Enzyme ◽  
Human Coronavirus ◽  
Angiotensin Converting Enzyme 2 ◽  
Similar Activity ◽  
Human Coronaviruses

ABSTRACT The human coronaviruses (CoVs) severe acute respiratory syndrome (SARS)-CoV and NL63 employ angiotensin-converting enzyme 2 (ACE2) for cell entry. It was shown that recombinant SARS-CoV spike protein (SARS-S) downregulates ACE2 expression and thereby promotes lung injury. Whether NL63-S exerts a similar activity is yet unknown. We found that recombinant SARS-S bound to ACE2 and induced ACE2 shedding with higher efficiency than NL63-S. Shedding most likely accounted for the previously observed ACE2 downregulation but was dispensable for viral replication. Finally, SARS-CoV but not NL63 replicated efficiently in ACE2-positive Vero cells and reduced ACE2 expression, indicating robust receptor interference in the context of SARS-CoV but not NL63 infection.

scholarly journals A model for pH coupling of the SARS-CoV-2 spike protein open/closed equilibrium

2021 ◽  
Author(s):  
Jim Warwicker
Keyword(s):  
Linoleic Acid ◽  
Severe Acute Respiratory Syndrome ◽  
Cell Surface ◽  
Ph Dependence ◽  
Salt Bridge ◽  
Spike Protein ◽  
Salt Bridges ◽  
Heat Map ◽  
Closed Conformation ◽  
Human Coronaviruses

Abstract Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), causative agent of the coronavirus disease 2019 (COVID-19) pandemic, is thought to release its RNA genome at either the cell surface or within endosomes, the balance being dependent on spike protein stability, and the complement of receptors, co-receptors and proteases. To investigate possible mediators of pH-dependence, pKa calculations have been made on a set of structures for spike protein ectodomain and fragments from SARS-CoV-2 and other coronaviruses. Dominating a heat map of the aggregated predictions, three histidine residues in S2 are consistently predicted as destabilizing in pre-fusion (all three) and post-fusion (two of the three) structures. Other predicted features include the more moderate energetics of surface salt–bridge interactions and sidechain–mainchain interactions. Two aspartic acid residues in partially buried salt-bridges (D290–R273 and R355–D398) have pKas that are calculated to be elevated and destabilizing in more open forms of the spike trimer. These aspartic acids are most stabilized in a tightly closed conformation that has been observed when linoleic acid is bound, and which also affects the interactions of D614. The D614G mutation is known to modulate the balance of closed to open trimer. It is suggested that D398 in particular contributes to a pH-dependence of the open/closed equilibrium, potentially coupled to the effects of linoleic acid binding and D614G mutation, and possibly also A570D mutation. These observations are discussed in the context of SARS-CoV-2 infection, mutagenesis studies, and other human coronaviruses.

scholarly journals Systematic evaluation of SARS-CoV-2 spike protein derived peptides for diagnosis of COVID-19 patients

2020 ◽  
Author(s):  
Yang Li ◽  
Danyun Lai ◽  
Qing Lei ◽  
Zhaowei Xu ◽  
Hongyan Hou ◽  
...  
Keyword(s):  
Serological Test ◽  
Protein S ◽  
Cross Reactivity ◽  
Spike Protein ◽  
Systematic Evaluation ◽  
Peptide Microarray ◽  
Serological Tests ◽  
S Protein ◽  
Asymptomatic Patients ◽  
Human Coronaviruses

Serological test plays an essential role in monitoring and combating COVID-19 pandemic. Recombinant spike protein (S protein), especially S1 protein is one of the major reagents for serological tests. However, the high cost in production of S protein, and the possible cross-reactivity with other human coronaviruses poses unneglectable challenges. Taking advantage of a peptide microarray of full spike protein coverage, we analyzed 2,434 sera from 858 COVID-19 patients, sera from 63 asymptomatic patients and 610 controls collected from multiple clinical centers. Based on the results of the peptide microarray, we identified several S protein derived 12-mer peptides that have high diagnosis performance. Particularly, for monitoring IgG response, one peptide (aa 1148-1159 or S2-78) has a comparable sensitivity (95.5%, 95% CI 93.7-96.9%) and specificity (96.7%, 95% CI 94.8-98.0%) to that of S1 protein for detection of both COVID-19 patients and asymptomatic infections. Furthermore, the performance of S2-78 IgG for diagnosis was successfully validated by ELISA with an independent sample cohort. By combining S2-78/ S1 with other peptides, a two-step strategy was proposed to ensure both the sensitivity and specificity of S protein based serological assay. The peptide/s identified in this study could be applied independently or in combination with S1 protein for accurate, affordable, and accessible COVID-19 diagnosis.

scholarly journals SARS-CoV-2 invades host cells via a novel route: CD147-spike protein

2020 ◽  
Author(s):  
Ke Wang ◽  
Wei Chen ◽  
Yu-Sen Zhou ◽  
Jian-Qi Lian ◽  
Zheng Zhang ◽  
...  
Keyword(s):  
Electron Microscope ◽  
Severe Acute Respiratory Syndrome ◽  
Research Finding ◽  
Antiviral Drugs ◽  
Host Cells ◽  
Spike Protein ◽  
Affinity Constant ◽  
Humanized Antibody ◽  
The World

SUMMARYCurrently, COVID-19 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been widely spread around the world; nevertheless, so far there exist no specific antiviral drugs for treatment of the disease, which poses great challenge to control and contain the virus. Here, we reported a research finding that SARS-CoV-2 invaded host cells via a novel route of CD147-spike protein (SP). SP bound to CD147, a receptor on the host cells, thereby mediating the viral invasion. Our further research confirmed this finding. First, in vitro antiviral tests indicated Meplazumab, an anti-CD147 humanized antibody, significantly inhibited the viruses from invading host cells, with an EC50 of 24.86 μg/mL and IC50 of 15.16 μg/mL. Second, we validated the interaction between CD147 and SP, with an affinity constant of 1.85×10−7M. Co-Immunoprecipitation and ELISA also confirmed the binding of the two proteins. Finally, the localization of CD147 and SP was observed in SARS-CoV-2 infected Vero E6 cells by immuno-electron microscope. Therefore, the discovery of the new route CD147-SP for SARS-CoV-2 invading host cells provides a critical target for development of specific antiviral drugs.

scholarly journals Development of a novel hybrid alphavirus-SARS-CoV-2 particle for rapid in vitro screening and quantification of neutralization antibodies, antiviral drugs, and viral mutations

2020 ◽  
Author(s):  
Brian Hetrick ◽  
Sijia He ◽  
Linda D. Chilin ◽  
Deemah Dabbagh ◽  
Farhang Alem ◽  
...  
Keyword(s):  
Viral Entry ◽  
Neutralizing Antibodies ◽  
Protein S ◽  
Antiviral Drugs ◽  
Spike Protein ◽  
Structural Proteins ◽  
Rapid Screening ◽  
Target Cells ◽  
Rapid Monitoring

SUMMARYTimely development of vaccines and antiviral drugs are critical to control the coronavirus disease 2019 (COVID-19) global pandemic 1–6. Current methods for validation of vaccine efficacy involve the use of pseudoviruses, such as the SARS-CoV-2 spike protein (S) pseudotyped lentivirus or vesicular stomatitis virus (VSV), to quantify neutralizing antibodies for blocking viral infection 7–14. The process of pseudovirus infection and quantification is time consuming and can take days to complete. In addition, pseudoviruses contain structural proteins not native to SARS-CoV-2, which may alter particle properties in receptor binding and responses to antibody neutralization 15. Here we describe the development of a new hybrid alphavirus-SARS-CoV-2 particle (Ha-CoV-2) for rapid screening and quantification of neutralization antibodies and antiviral drugs. Ha-CoV-2 is a non-replicating SARS-CoV-2 virus-like particle, composed of only SARS-CoV-2 structural proteins (S, M, N, and E) and a RNA genome derived from a fast expressing alphavirus vector 16. We demonstrate that Ha-CoV-2 can rapidly and robustly express reporter genes in target cells within 3-5 hours following viral entry. We further validate the Ha-CoV-2 system for rapid quantification of neutralization antibodies and antiviral drugs. In addition, we assembled a Ha-CoV-2 particle bearing the D614G mutant spike protein, and found that the mutation led to an approximately 200% increase in virion infectivity. These results demonstrate that Ha-CoV-2 can also be applied for rapid monitoring and quantification of viral mutations for effects on neutralizing antibodies induced by vaccines.

scholarly journals SARS hCoV papain-like protease is a unique Lys48 linkage-specific di-distributive deubiquitinating enzyme

2015 ◽  
Vol 468 (2) ◽  
pp. 215-226 ◽  
Author(s):  
Miklós Békés ◽  
Wioletta Rut ◽  
Paulina Kasperkiewicz ◽  
Monique P.C. Mulder ◽  
Huib Ovaa ◽  
...  
Keyword(s):  
Middle East ◽  
Severe Acute Respiratory Syndrome ◽  
Signaling Molecules ◽  
Middle East Respiratory Syndrome ◽  
Deubiquitinating Enzyme ◽  
Substrate Specificities ◽  
Unique Mode ◽  
Interferon Stimulated Gene 15 ◽  
Human Coronaviruses

We compare processing proteases from two human coronaviruses - the severe acute respiratory syndrome (SARS) and the Middle East respiratory syndrome (MERS) hCoVs - with respect to their activities and substrate specificities for ubiquitin (Ub)-like signaling molecules, Ub and ISG15 (interferon stimulated gene 15); and doing so, we uncover a unique mode of polyUb recognition by the SARS protease.

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