scholarly journals An emerging SARS-CoV-2 mutant evading cellular immunity and increasing viral infectivity

2021 ◽  
Author(s):  
Chihiro Motozono ◽  
Mako Toyoda ◽  
Jiri Zahradnik ◽  
Terumasa Ikeda ◽  
Akatsuki Saito ◽  
...  
Keyword(s):  
Receptor Binding ◽  
Cellular Immunity ◽  
Human Leukocyte ◽  
Spike Protein ◽  
Viral Infectivity ◽  
Receptor Binding Domain ◽  
Viral Receptor ◽  
Leukocyte Antigen ◽  
Immune Resistance ◽  
Naturally Occurring

SummaryDuring the current SARS-CoV-2 pandemic that is devastating the modern societies worldwide, many variants that naturally acquire multiple mutations have emerged. Emerging mutations can affect viral properties such as infectivity and immune resistance. Although the sensitivity of naturally occurring SARS-CoV-2 variants to humoral immunity has recently been investigated, that to human leukocyte antigen (HLA)-restricted cellular immunity remains unaddressed. Here we demonstrate that two recently emerging mutants in the receptor binding domain of the SARS-CoV-2 spike protein, L452R (in B.1.427/429) and Y453F (in B.1.298), can escape from the HLA-24-restricted cellular immunity. These mutations reinforce the affinity to viral receptor ACE2, and notably, the L452R mutation increases protein stability, viral infectivity, and potentially promotes viral replication. Our data suggest that the HLA-restricted cellular immunity potentially affects the evolution of viral phenotypes, and the escape from cellular immunity can be a further threat of the SARS-CoV-2 pandemic.Graphical Abstract

Heteromerization As a Mechanism Modulating the Affinity of the ACE2 Receptor to the Receptor Binding Domain of SARS-CoV-2 Spike Protein

2020 ◽  
Vol 18 ◽  
Author(s):  
Diego Guidolin ◽  
Cinzia Tortorella ◽  
Deanna Anderlini ◽  
Manuela Marcoli ◽  
Guido Maura
Keyword(s):  
Receptor Binding ◽  
Binding Domain ◽  
G Protein Coupled Receptors ◽  
Spike Protein ◽  
Macromolecular Complex ◽  
Receptor Binding Domain ◽  
Viral Receptor ◽  
Angiotensin Converting Enzyme 2 ◽  
Quaternary Structures ◽  
G Protein Coupled

Background: Angiotensin Converting Enzyme 2 (ACE2) is primarily involved in the maturation of angiotensin. It also represents the main receptor for the Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2) that caused the serious epidemics COVID-19. Available evidence indicates that at the cell membrane ACE2 can form heteromeric complexes with other membrane proteins, including the amino acid transporter B0AT1 and G Protein-Coupled Receptors (GPCR). Objective: It is well known that during the formation of quaternary structures, the configuration of each single monomer is re-shaped by its interaction pattern in the macromolecular complex. Therefore, it can be hypothesized that the affinity of ACE2 to the viral receptor binding domain (RBD), when in a heteromeric complex, may depend on the associated partner. Method: By using established docking and molecular dynamics procedures, the reshaping of monomer was explored in silico to predict possible heterodimeric structures between ACE2 and GPCR, such as angiotensin and bradykinin receptors. The associated possible changes in binding affinity between the viral RBD and ACE2 when in the heteromeric complexes were also estimated. Results and Conclusion: The results provided support to the hypothesis that the heteromerization state of ACE2 may modulate its affinity to the viral RBD. If experimentally confirmed, ACE2 heteromerization may contribute to explain the observed differences in susceptibility to virus infection among individuals and to devise new therapeutic opportunities.

scholarly journals SARS-CoV-2 Prion-Like Domains in Spike Proteins Enables Higher Affinity to ACE2

2020 ◽  
Author(s):  
George Tetz ◽  
Victor Tetz
Keyword(s):  
Receptor Binding ◽  
Cell Receptor ◽  
Binding Domain ◽  
Spike Protein ◽  
Striking Difference ◽  
Receptor Binding Domain ◽  
Viral Receptor ◽  
Functional Roles ◽  
Binding Domains ◽  
Spike Proteins

Currently, the world is struggling with the coronavirus disease 2019 (COVID-19) pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Prion-like domains are critical for virulence and the development of therapeutic targets; however, the prion-like domains in the SARS-CoV-2 proteome have not been analyzed. In this in silico study, using the PLAAC algorithm, we identified the presence of prion-like domains in SARS-CoV-2 spike protein. Compared with other viruses, a striking difference was observed in the distribution of prion-like domains in the spike, since SARS-CoV-2 was the only coronavirus with a prion-like domain found in the receptor-binding domain of the S1 region of the spike protein. The presence and unique distribution of prion-like domains in the SARS-CoV-2 receptor-binding domains of spike proteins is particularly interesting, since although SARS-CoV-2 and SARS-CoV S share the same host cell receptor, angiotensin-converting enzyme 2 (ACE2), SARS-CoV-2 demonstrates a 10- to 20-fold higher affinity for ACE2. Finally, we identified prion-like domains in the α1 helix of the ACE2 receptor that interacts with the viral receptor-binding domain of SARS-CoV-2. Taken together, the present findings indicate that the identified PrDs in the SARS-CoV-2 receptor-binding domain (RBD) and ACE2 region that interacts with RBD have important functional roles in viral adhesion and entry.

scholarly journals Development of a COVID-19 vaccine based on the receptor binding domain displayed on virus-like particles

2020 ◽  
Author(s):  
Lisha Zha ◽  
Hongxin Zhao ◽  
Mona O. Mohsen ◽  
Liang Hong ◽  
Yuhang Zhou ◽  
...  
Keyword(s):  
Receptor Binding ◽  
Vaccine Candidate ◽  
Rapid Development ◽  
Binding Domain ◽  
Spike Protein ◽  
Receptor Binding Domain ◽  
Viral Receptor ◽  
Virus Like Particles ◽  
The City

AbstractThe recently ermerging disease COVID-19 is caused by the new SARS-CoV-2 virus first detected in the city of Wuhan, China. From there it has been rapidly spreading inside and outside China. With initial death rates around 4%, COVID-19 patients at longer distances from Wuhan showed reduced mortality as was previously observed for the SARS coronavirus. However, the new coronavirus spreads more strongly, as it sheds long before onset of symptoms or may be transmitted by people without symptoms. Rapid development of a protective vaccine against COVID-19 is therefore of paramount importance. Here we demonstrate that recombinantly expressed receptor binding domain (RBD) of the spike protein homologous to SARS binds to ACE2, the viral receptor. Higly repetitive display of RBD on immunologically optimized virus-like particles derived from cucumber mosaic virus resulted in a vaccine candidate (RBD-CuMVTT) that induced high levels of specific antibodies in mice which were able to block binding of spike protein to ACE2 and potently neutralized the SARS-CoV-2 virus in vitro.

scholarly journals Development of a Vaccine against SARS-CoV-2 Based on the Receptor-Binding Domain Displayed on Virus-Like Particles

Vaccines ◽  
2021 ◽  
Vol 9 (4) ◽  
pp. 395
Author(s):  
Lisha Zha ◽  
Xinyue Chang ◽  
Hongxin Zhao ◽  
Mona O. Mohsen ◽  
Liang Hong ◽  
...  
Keyword(s):  
Receptor Binding ◽  
Rapid Development ◽  
Binding Domain ◽  
Spike Protein ◽  
Receptor Binding Domain ◽  
Viral Receptor ◽  
Major Health ◽  
Virus Like Particles

The ongoing coronavirus disease (COVID-19) pandemic is caused by a new coronavirus (severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2)) first reported in Wuhan City, China. From there, it has been rapidly spreading to many cities inside and outside China. Nowadays, more than 110 million cases with deaths surpassing 2 million have been recorded worldwide, thus representing a major health and economic issues. Rapid development of a protective vaccine against COVID-19 is therefore of paramount importance. Here, we demonstrated that the recombinantly expressed receptor-binding domain (RBD) of the spike protein can be coupled to immunologically optimized virus-like particles derived from cucumber mosaic virus (CuMVTT). The RBD displayed CuMVTT bound to ACE2, the viral receptor, demonstrating proper folding of RBD. Furthermore, a highly repetitive display of the RBD on CuMVTT resulted in a vaccine candidate that induced high levels of specific antibodies in mice, which were able to block binding of the spike protein to ACE2 and potently neutralize SARS-CoV-2 virus in vitro.

scholarly journals Stereotypic neutralizing VH antibodies against SARS-CoV-2 spike protein receptor binding domain in COVID-19 patients and healthy individuals

2021 ◽  
pp. eabd6990
Author(s):  
Sang Il Kim ◽  
Jinsung Noh ◽  
Sujeong Kim ◽  
Younggeun Choi ◽  
Duck Kyun Yoo ◽  
...  
Keyword(s):  
B Cells ◽  
Receptor Binding ◽  
Neutralizing Antibodies ◽  
De Novo ◽  
Binding Domain ◽  
Host Cells ◽  
Spike Protein ◽  
Receptor Binding Domain ◽  
Healthy Individuals

Stereotypic antibody clonotypes exist in healthy individuals and may provide protective immunity against viral infections by neutralization. We observed that 13 out of 17 patients with COVID-19 had stereotypic variable heavy chain (VH) antibody clonotypes directed against the receptor-binding domain (RBD) of SARS-CoV-2 spike protein. These antibody clonotypes were comprised of immunoglobulin heavy variable (IGHV)3-53 or IGHV3-66 and immunoglobulin heavy joining (IGHJ)6 genes. These clonotypes included IgM, IgG3, IgG1, IgA1, IgG2, and IgA2 subtypes and had minimal somatic mutations, which suggested swift class switching after SARS-CoV-2 infection. The different immunoglobulin heavy variable chains were paired with diverse light chains resulting in binding to the RBD of SARS-CoV-2 spike protein. Human antibodies specific for the RBD can neutralize SARS-CoV-2 by inhibiting entry into host cells. We observed that one of these stereotypic neutralizing antibodies could inhibit viral replication in vitro using a clinical isolate of SARS-CoV-2. We also found that these VH clonotypes existed in six out of 10 healthy individuals, with IgM isotypes predominating. These findings suggest that stereotypic clonotypes can develop de novo from naïve B cells and not from memory B cells established from prior exposure to similar viruses. The expeditious and stereotypic expansion of these clonotypes may have occurred in patients infected with SARS-CoV-2 because they were already present.

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