scholarly journals An Autochthonous Outbreak of the SARS-CoV-2 P.1 Variant of Concern in Southern Italy, April 2021

2021 ◽  
Vol 6 (3) ◽  
pp. 151
Author(s):  
Daniela Loconsole ◽  
Anna Sallustio ◽  
Francesca Centrone ◽  
Daniele Casulli ◽  
Maurizio Mario Ferrara ◽  
...  
Keyword(s):  
Neutralizing Antibodies ◽  
Clinical Presentation ◽  
Southern Italy ◽  
Receptor Binding Domain ◽  
Gene Target ◽  
Health Measures ◽  
Molecular Tests ◽  
Laboratory Investigations ◽  
The Impact ◽  
Mild Clinical Presentation

The SARS-CoV-2 P.1 variant of concern (VOC) was first identified in Brazil and is now spreading in European countries. It is characterized by the E484K mutation in the receptor-binding domain, which could contribute to the evasion from neutralizing antibodies. In Italy, this variant was first identified in January 2021. Here, we report an autochthonous outbreak of SARS-CoV-2 P.1 variant infections in southern Italy in subjects who had not travelled to endemic areas or outside the Apulia region. The outbreak involved seven subjects, three of whom had received a COVID-19 vaccine (one had received two doses and two had received one dose). Four patients had a mild clinical presentation. Laboratory investigations of nasopharyngeal swabs revealed that all strains were S-gene target failure-negative and molecular tests revealed they were the P.1 variant. Whole-genome sequencing confirmed that five subjects were infected with closely related strains classified as the P.1 lineage. The circulation of VOCs highlights the importance of strictly monitoring the spread of SARS-CoV-2 variants through genomic surveillance and of investigating local outbreaks. Furthermore, public health measures including social distancing, screening, and quarantine for travelers are key tools to slow down the viral transmission and to contain and mitigate the impact of VOC diffusion, and rapid scaling-up of vaccination is crucial to avoid a possible new epidemic wave.

scholarly journals The Impact on Infectivity and Neutralization Efficiency of SARS-CoV-2 Lineage B.1.351 Pseudovirus

Viruses ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 633
Author(s):  
Yeong Jun Kim ◽  
Ui Soon Jang ◽  
Sandrine M. Soh ◽  
Joo-Youn Lee ◽  
Hye-Ra Lee
Keyword(s):  
South Africa ◽  
Monoclonal Antibodies ◽  
Cell Fusion ◽  
Receptor Binding ◽  
Neutralizing Antibodies ◽  
Receptor Binding Domain ◽  
Viral Spread ◽  
New Variant ◽  
Global Concern ◽  
The Impact

A new variant of SARS-CoV-2 B.1.351 lineage (first found in South Africa) has been raising global concern due to its harboring of multiple mutations in the spike that potentially increase transmissibility and yield resistance to neutralizing antibodies. We here tested infectivity and neutralization efficiency of SARS-CoV-2 spike pseudoviruses bearing particular mutations of the receptor-binding domain (RBD) derived either from the Wuhan strains (referred to as D614G or with other sites) or the B.1.351 lineage (referred to as N501Y, K417N, and E484K). The three different pseudoviruses B.1.351 lineage related significantly increased infectivity compared with other mutants that indicated Wuhan strains. Interestingly, K417N and E484K mutations dramatically enhanced cell–cell fusion than N501Y even though their infectivity were similar, suggesting that K417N and E484K mutations harboring SARS-CoV-2 variant might be more transmissible than N501Y mutation containing SARS-CoV-2 variant. We also investigated the efficacy of two different monoclonal antibodies, Casirivimab and Imdevimab that neutralized SARS-CoV-2, against several kinds of pseudoviruses which indicated Wuhan or B.1.351 lineage. Remarkably, Imdevimab effectively neutralized B.1.351 lineage pseudoviruses containing N501Y, K417N, and E484K mutations, while Casirivimab partially affected them. Overall, our results underscore the importance of B.1.351 lineage SARS-CoV-2 in the viral spread and its implication for antibody efficacy.

scholarly journals Epistasis at the SARS-CoV-2 RBD Interface and the Propitiously Boring Implications for Vaccine Escape

2021 ◽  
Author(s):  
Nash D. Rochman ◽  
Guilhem Faure ◽  
Yuri I. Wolf ◽  
Peter L. Freddolino ◽  
Feng Zhang ◽  
...  
Keyword(s):  
Receptor Binding ◽  
Neutralizing Antibodies ◽  
Binding Domain ◽  
Receptor Binding Domain ◽  
Wild Type ◽  
Protein Structure Modeling ◽  
Escape Mutants ◽  
Small Set ◽  
Global Concern ◽  
The Impact

AbstractAt the time of this writing, August 2021, potential emergence of vaccine escape variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a grave global concern. The interface between the receptor-binding domain (RBD) of SARS-CoV-2 spike (S) protein and the host receptor (ACE2) overlap with the binding site of principal neutralizing antibodies (NAb), limiting the repertoire of viable mutations. Nonetheless, variants with multiple mutations in the RBD have rose to dominance. Non-additive, epistatic relationships among RBD mutations are apparent, and assessing the impact of such epistasis on the mutational landscape is crucial. Epistasis can substantially increase the risk of vaccine escape and cannot be completely characterized through the study of the wild type (WT) alone. We employed protein structure modeling using Rosetta to compare the effects of all single mutants at the RBD-NAb and RBD-ACE2 interfaces for the WT, Gamma (417T, 484K, 501Y), and Delta variants (452R, 478K). Overall, epistasis at the RBD surface appears to be limited and the effects of most multiple mutations are additive. Epistasis at the Delta variant interface weakly stabilizes NAb interaction relative to ACE2, whereas in the Gamma variant, epistasis more substantially destabilizes NAb interaction. These results suggest that the repertoire of potential escape mutations for the Delta variant is not substantially different from that of the WT, whereas Gamma poses a moderately greater risk for enhanced vaccine escape. Thus, the modest ensemble of mutations relative to the WT shown to reduce vaccine efficacy might constitute the majority of all possible escape mutations.SignificancePotential emergence of vaccine escape variants of SARS-CoV-2 is arguably the most pressing problem during the COVID-19 pandemic as vaccines are distributed worldwide. We employed a computational approach to assess the risk of antibody escape resulting from mutations in the receptor-binding domain of the spike protein of the wild type SARS-CoV-2 virus as well as the Gamma and Delta variants. The results indicate that emergence of escape mutants is somewhat less likely for the Delta variant than for the wild type and moderately more likely for the Gamma variant. We conclude that the small set of escape-enhancing mutations already identified for the wild type is likely to include the majority of all possible mutations with this effect, a welcome finding.

scholarly journals Structural and energetic profiling of SARS-CoV-2 antibody recognition and the impact of circulating variants

2021 ◽  
Author(s):  
Rui Yin ◽  
Johnathan D Guest ◽  
Ghazaleh Taherzadeh ◽  
Ragul Gowthaman ◽  
Ipsa Mittra ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
Neutralizing Antibodies ◽  
Antibody Responses ◽  
Receptor Binding Domain ◽  
Design Strategies ◽  
Detailed Structure ◽  
Viral Variant ◽  
Antibody Recognition ◽  
The Impact ◽  
Binding Determinants

The SARS-CoV-2 pandemic highlights the need for a detailed molecular understanding of protective antibody responses. This is underscored by the emergence and spread of SARS-CoV-2 variants, including B.1.1.7, P1, and B.1.351, some of which appear to be less effectively targeted by current monoclonal antibodies and vaccines. Here we report a high resolution and comprehensive map of antibody recognition of the SARS-CoV-2 spike receptor binding domain (RBD), which is the target of most neutralizing antibodies, using computational structural analysis. With a dataset of nonredundant experimentally determined antibody-RBD structures, we classified antibodies by RBD residue binding determinants using unsupervised clustering. We also identified the energetic and conservation features of epitope residues and assessed the capacity of viral variant mutations to disrupt antibody recognition, revealing sets of antibodies predicted to effectively target recently described viral variants. This detailed structure-based reference of antibody RBD recognition signatures can inform therapeutic and vaccine design strategies.

scholarly journals Structural and energetic profiling of SARS-CoV-2 receptor binding domain antibody recognition and the impact of circulating variants

2021 ◽  
Vol 17 (9) ◽  
pp. e1009380
Author(s):  
Rui Yin ◽  
Johnathan D. Guest ◽  
Ghazaleh Taherzadeh ◽  
Ragul Gowthaman ◽  
Ipsa Mittra ◽  
...  
Keyword(s):  
Receptor Binding ◽  
Neutralizing Antibodies ◽  
Binding Domain ◽  
Receptor Binding Domain ◽  
Design Strategies ◽  
Detailed Structure ◽  
Antibody Recognition ◽  
Domain Antibody ◽  
The Impact ◽  
Binding Determinants

The SARS-CoV-2 pandemic highlights the need for a detailed molecular understanding of protective antibody responses. This is underscored by the emergence and spread of SARS-CoV-2 variants, including Alpha (B.1.1.7) and Delta (B.1.617.2), some of which appear to be less effectively targeted by current monoclonal antibodies and vaccines. Here we report a high resolution and comprehensive map of antibody recognition of the SARS-CoV-2 spike receptor binding domain (RBD), which is the target of most neutralizing antibodies, using computational structural analysis. With a dataset of nonredundant experimentally determined antibody-RBD structures, we classified antibodies by RBD residue binding determinants using unsupervised clustering. We also identified the energetic and conservation features of epitope residues and assessed the capacity of viral variant mutations to disrupt antibody recognition, revealing sets of antibodies predicted to effectively target recently described viral variants. This detailed structure-based reference of antibody RBD recognition signatures can inform therapeutic and vaccine design strategies.

scholarly journals Impact of the SARS-CoV-2 S-protein G476S mutation on the interaction with human ACE-2 receptor and neutralizing antibodies

2021 ◽  
Author(s):  
Alexander Kwarteng ◽  
Ebenezer Asiedu ◽  
Augustina Angelina Sylverken ◽  
Amma Larbi ◽  
Peter Twumasi
Keyword(s):  
Receptor Binding ◽  
Neutralizing Antibodies ◽  
Similar Efficacy ◽  
Receptor Binding Domain ◽  
S Protein ◽  
Angiotensin Converting Enzyme 2 ◽  
Main Target ◽  
The Usa ◽  
Binding Residues ◽  
The Impact

Abstract The G476S mutation of the SARS-CoV-2 S-protein occurs in the receptor binding domain (RBD), the region that binds to the human angiotensin-converting enzyme 2 (hACE-2) receptor and also the main target for neutralizing antibodies. The 476S variant was first reported in the USA. Emerging evidence show that the 476S variant resists neutralization by antibodies such as S2E12 and CC6.29. The impact of the mutation on the interactions with hACE-2 receptor and the dynamics of the S-protein, has not been not fully explored. Here, we provide insights into the structure dynamics of the 476S variant and investigate the impact of the mutation on interactions with hACE-2 and selected neutralizing antibodies. We report that the mutation induces a destabilization effect in the RBD and an increased flexibility for most of the receptor binding residues. The mutation, however, does not affect the interactions with the hACE-2 receptor. Both Gly-476 and Ser-476, although located within the hACE-2 interacting residue hotspot, do not contribute to the stabilization of the RBD-hACE-2 complex. Our findings suggest that both H014 and P2P-2F6 antibodies neutralize the 476G and 476S S-proteins with similar efficacy.

scholarly journals Altered Local Interactions and Long-Range Communications in UK Variant (B.1.1.7) Spike Glycoprotein

2021 ◽  
Vol 22 (11) ◽  
pp. 5464
Author(s):  
Stefano Borocci ◽  
Carmen Cerchia ◽  
Alessandro Grottesi ◽  
Nico Sanna ◽  
Ingrid Guarnetti Prandi ◽  
...  
Keyword(s):  
Neutralizing Antibodies ◽  
Structural Information ◽  
Conformational Transitions ◽  
Structural Basis ◽  
Receptor Binding Domain ◽  
Wild Type ◽  
Dynamics Simulations ◽  
The Uk ◽  
The Impact

The COVID-19 pandemic is caused by SARS-CoV-2. Currently, most of the research efforts towards the development of vaccines and antibodies against SARS-CoV-2 were mainly focused on the spike (S) protein, which mediates virus entry into the host cell by binding to ACE2. As the virus SARS-CoV-2 continues to spread globally, variants have emerged, characterized by multiple mutations of the S glycoprotein. Herein, we employed microsecond-long molecular dynamics simulations to study the impact of the mutations of the S glycoprotein in SARS-CoV-2 Variant of Concern 202012/01 (B.1.1.7), termed the “UK variant”, in comparison with the wild type, with the aim to decipher the structural basis of the reported increased infectivity and virulence. The simulations provided insights on the different dynamics of UK and wild-type S glycoprotein, regarding in particular the Receptor Binding Domain (RBD). In addition, we investigated the role of glycans in modulating the conformational transitions of the RBD. The overall results showed that the UK mutant experiences higher flexibility in the RBD with respect to wild type; this behavior might be correlated with the increased transmission reported for this variant. Our work also adds useful structural information on antigenic “hotspots” and epitopes targeted by neutralizing antibodies.

Alteraciones sistémicas y metabólicas producidas por lesión medular

2019 ◽  
Vol 1 (1) ◽  
pp. 59-75
Author(s):  
Gabriel Guízar Sahagún
Keyword(s):  
Spinal Cord ◽  
Daily Living ◽  
Autonomic Function ◽  
Clinical Presentation ◽  
Scientific Literature ◽  
International Standards ◽  
Therapeutic Approaches ◽  
Cord Injury ◽  
Life Threatening ◽  
The Impact

Besides the well-known loss of motor and sensory capabilities, people with spinal cord injury (SCI) experience a broad range of systemic and metabolic abnormalities including, among others, dysfunction of cardiovascular, respiratory, gastrointestinal, urinary, and endocrine systems. These alterations are a significant challenge for patients with SCI because such disorders severely interfere with their daily living and can be potentially life-threatening. Most of these disorders are associated with impairment of regulation of the autonomic nervous system, arising from disruption of connections between higher brain centers and the spinal cord caudal to the injured zone. Thus, the higher and more complete the lesion, the greater the autonomic dysfunction and the severity of complications.This article summarizes the medical scientific literature on key systemic and metabolic alterations derived of SCI. It provides information primarily focused on the pathophysiology and clinical presentation of these disorders, as well as some guides to prevent and alleviate such complications. Due to the impact of these alterations, this topic must be a priority and diffuse to those involved with the care of people with SCI, including the patient himself/herself. We consider that any collaborative effort should be supported, like the development of international standards, to evaluate autonomic function after SCI, as well as the development of novel therapeutic approaches.

scholarly journals Emotional and Mental Wellbeing Following COVID-19 Public Health Measures on People Living With Dementia and Carers

2021 ◽  
pp. 089198872199681
Author(s):  
Kerry Hanna ◽  
Clarissa Giebel ◽  
Hilary Tetlow ◽  
Kym Ward ◽  
Justine Shenton ◽  
...  
Keyword(s):  
Public Health ◽  
Mental Health ◽  
Social Support ◽  
Support Services ◽  
Mental Wellbeing ◽  
Daily Lives ◽  
Health Measures ◽  
Social Support Services ◽  
The Uk ◽  
The Impact

Background: To date, there appears to be no evidence on the longer-term impacts caused by COVID-19 and its related public health restrictions on some of the most vulnerable in our societies. The aim of this research was to explore the change in impact of COVID-19 public health measures on the mental wellbeing of people living with dementia (PLWD) and unpaid carers. Method: Semi-structured, follow-up telephone interviews were conducted with PLWD and unpaid carers between June and July 2020. Participants were asked about their experiences of accessing social support services during the pandemic, and the impact of restrictions on their daily lives. Results: 20 interviews were conducted and thematically analyzed, which produced 3 primary themes concerning emotional responses and impact to mental health and wellbeing during the course of the pandemic: 1) Impact on mental health during lockdown, 2) Changes to mental health following easing of public health, and 3) The long-term effect of public health measures. Conclusions: The findings from this research shed light on the longer-term psychological impacts of the UK Government’s public health measures on PLWD and their carers. The loss of social support services was key in impacting this cohort mentally and emotionally, displaying a need for better psychological support, for both carers and PLWD.

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.

Clinical presentation of a stroke-like episode in MELAS syndrome: what is the impact of epileptogenic activity?

2021 ◽  
Author(s):  
Pia Bernardo ◽  
Maria Pandolfi ◽  
Paola Vedova ◽  
Antonio Varone ◽  
Alfonso Rubino
Keyword(s):  
Clinical Presentation ◽  
Melas Syndrome ◽  
The Impact
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