Cryo-EM structures of SARS-CoV-2 Omicron BA.2 spike DOI Creative Commons
Victoria Stalls, Jared Lindenberger, S. Gobeil

et al.

Cell Reports, Journal Year: 2022, Volume and Issue: 39(13), P. 111009 - 111009

Published: June 1, 2022

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron BA.2 sub-lineage has gained in proportion relative to BA.1. Because spike (S) protein variations may underlie differences their pathobiology, here we determine cryoelectron microscopy (cryo-EM) structures of the S ectodomain and compare these with previously determined BA.1 structures. receptor-binding domain (RBD) mutations induce remodeling RBD structure, resulting tighter packing improved thermostability. Interprotomer interactions are enhanced closed (or 3-RBD-down) S, while fusion peptide is less accessible antibodies than Binding pseudovirus neutralization assays reveal extensive immune evasion defining epitopes two outer face-binding antibodies, DH1044 DH1193, that neutralize both BA.2. Taken together, our results indicate stabilization state through interprotomer RBD-RBD a hallmark variant show key functional regions proteins.

Language: Английский

Structural diversity of the SARS-CoV-2 Omicron spike DOI Creative Commons
S. Gobeil, Rory Henderson, Victoria Stalls

et al.

Molecular Cell, Journal Year: 2022, Volume and Issue: 82(11), P. 2050 - 2068.e6

Published: March 25, 2022

Language: Английский

Citations

179
Immune dysregulation and immunopathology induced by SARS-CoV-2 and related coronaviruses — are we our own worst enemy? DOI Creative Commons
Lok-Yin Roy Wong, Stanley Perlman

Nature reviews. Immunology, Journal Year: 2021, Volume and Issue: 22(1), P. 47 - 56

Published: Nov. 26, 2021

Human coronaviruses cause a wide spectrum of disease, ranging from mild common colds to acute respiratory distress syndrome and death. Three highly pathogenic human — severe coronavirus (SARS-CoV), Middle East SARS-CoV-2 have illustrated the epidemic pandemic potential coronaviruses, better understanding their disease-causing mechanisms is urgently needed for rational design therapeutics. Analyses patients revealed marked dysregulation immune system in cases infection, there ample evidence that aberrant responses are typified by impaired induction interferons, exuberant inflammatory delayed adaptive responses. In addition, various viral proteins been shown impair interferon signalling induce inflammasome activation. This suggests disease associated with mediated both dysregulated host active interference. Here we discuss our current involved each these scenarios. this Perspective, Lok-Yin Roy Wong Stanley Perlman consider how 2 (SARS-CoV-2) related able drive immunopathology. They provide an overview coronavirus-derived molecules interfere key innate responses, including pathways complement, NF-κB activation, as well activation immunity.

Language: Английский

Citations

164
Characterization of the enhanced infectivity and antibody evasion of Omicron BA.2.75 DOI Creative Commons
Yunlong Cao,

Weiliang Song,

Lei Wang

et al.

Cell Host & Microbe, Journal Year: 2022, Volume and Issue: 30(11), P. 1527 - 1539.e5

Published: Oct. 4, 2022

Recently emerged SARS-CoV-2 Omicron subvariant, BA.2.75, displayed a growth advantage over circulating BA.2.38, BA.2.76, and BA.5 in India. However, the underlying mechanisms for enhanced infectivity, especially compared with BA.5, remain unclear. Here, we show that BA.2.75 exhibits substantially higher affinity host receptor angiotensin-converting enzyme 2 (ACE2) than other variants. Structural analyses of spike shows its decreased thermostability increased frequency binding domain (RBD) "up" conformation under acidic conditions, suggesting low-pH-endosomal cell entry. Relative to BA.4/BA.5, reduced evasion humoral immunity from BA.1/BA.2 breakthrough-infection convalescent plasma but greater Delta plasma. also weaker neutralization against mainly due BA.2.75's distinct neutralizing antibody (NAb) escape pattern. Antibody therapeutics Evusheld Bebtelovimab effective BA.2.75. These results suggest may prevail after receptor-binding capability could support further immune-evasive mutations.

Language: Английский

Citations

159
The humoral response and antibodies against SARS-CoV-2 infection DOI Open Access
Hai Qi,

Bo Liu,

Xinquan Wang

et al.

Nature Immunology, Journal Year: 2022, Volume and Issue: 23(7), P. 1008 - 1020

Published: June 27, 2022

Language: Английский

Citations

150
Avidity in antibody effector functions and biotherapeutic drug design DOI Creative Commons
Simone C. Oostindie, Greg A. Lazar, Janine Schuurman

et al.

Nature Reviews Drug Discovery, Journal Year: 2022, Volume and Issue: 21(10), P. 715 - 735

Published: July 5, 2022

Antibodies are the cardinal effector molecules of immune system and being leveraged with enormous success as biotherapeutic drugs. A key part adaptive response is production an epitope-diverse, polyclonal antibody mixture that capable neutralizing invading pathogens or disease-causing through binding interference by mediating humoral cellular functions. Avidity — accumulated strength derived from affinities multiple individual non-covalent interactions fundamental to virtually all aspects biology, including antibody–antigen binding, clonal selection The manipulation avidity has since emerged important design principle for enhancing engineering novel properties in biotherapeutics. In this Review, we describe levels trigger overall efficacy control functional responses both natural biology their therapeutic applications. Within framework, comprehensively review mechanisms action, particular emphasis on engineered optimizations platforms. Overall, how affinity tuning formats enabling a new wave differentiated drugs tailored functions, promising improved treatment options wide variety diseases. Antibody function dependent between antibody, antigen, cell surface receptors other antibodies. Oostindie et al. discuss role eliciting current strategies manipulating antibody-based therapies.

Language: Английский

Citations

145
SARS-CoV-2 Neutralizing Antibodies for COVID-19 Prevention and Treatment DOI Open Access
Dapeng Li, Gregory D. Sempowski, Kevin O. Saunders

et al.

Annual Review of Medicine, Journal Year: 2021, Volume and Issue: 73(1), P. 1 - 16

Published: Aug. 24, 2021

Prophylactic and therapeutic drugs are urgently needed to combat coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome 2 (SARS-CoV-2). Over the past year, SARS-CoV-2 neutralizing antibodies have been developed for preventive or uses. While target spike protein, their neutralization potency breadth vary according recognition epitopes. Several potent shown degrees of success in preclinical clinical trials, US Food Drug Administration has issued emergency use authorization two antibody cocktails.Nevertheless, therapy still faces potential challenges, including emerging viral variants concern that antibody-escape mutations antibody-mediated enhancement infection inflammation. This review summarizes representative reported discusses prospects challenges development next generation COVID-19 antibodies.

Language: Английский

Citations

133
Analysis of memory B cells identifies conserved neutralizing epitopes on the N-terminal domain of variant SARS-Cov-2 spike proteins DOI Creative Commons
Zijun Wang,

Frauke Muecksch,

Alice Cho

et al.

Immunity, Journal Year: 2022, Volume and Issue: 55(6), P. 998 - 1012.e8

Published: April 7, 2022

SARS-CoV-2 infection or vaccination produces neutralizing antibody responses that contribute to better clinical outcomes. The receptor-binding domain (RBD) and the N-terminal (NTD) of spike trimer (S) constitute two major targets for antibodies. Here, we use NTD-specific probes capture anti-NTD memory B cells in a longitudinal cohort infected individuals, some whom were vaccinated. We found 6 complementation groups 58% targeted epitopes outside NTD supersite, neutralized either Gamma Omicron, 14% broad neutralizers also Omicron. Structural characterization revealed broadly active antibodies three supersite including class recognized both SD2 domain. Rapid recruitment producing these into plasma cell compartment upon re-infection likely contributes relatively benign course subsequent infections with variants,

Language: Английский

Citations

133
Antibody-mediated neutralization of SARS-CoV-2 DOI Creative Commons

Henning Gruell,

Kanika Vanshylla, Timm Weber

et al.

Immunity, Journal Year: 2022, Volume and Issue: 55(6), P. 925 - 944

Published: May 13, 2022

Language: Английский

Citations

120
Molecular characteristics, immune evasion, and impact of SARS-CoV-2 variants DOI Creative Commons
Cong Sun, Chu Xie,

Guo‐Long Bu

et al.

Signal Transduction and Targeted Therapy, Journal Year: 2022, Volume and Issue: 7(1)

Published: June 28, 2022

Abstract The persistent COVID-19 pandemic since 2020 has brought an enormous public health burden to the global society and is accompanied by various evolution of virus genome. consistently emerging SARS-CoV-2 variants harboring critical mutations impact molecular characteristics viral proteins display heterogeneous behaviors in immune evasion, transmissibility, clinical manifestation during infection, which differ each strain endow them with distinguished features populational spread. Several variants, identified as Variants Concern (VOC) World Health Organization, challenged efforts on control due rapid worldwide spread enhanced evasion from current antibodies vaccines. Moreover, recent Omicron variant even exacerbated anxiety continuous pandemic. Its significant medical treatment disease highlights necessity combinatory investigation mutational pattern influence dynamics against immunity, would greatly facilitate drug vaccine development benefit policymaking. Hence this review, we summarized characteristics, impacts focused parallel comparison different profile, transmissibility tropism alteration, effectiveness, manifestations, order provide a comprehensive landscape for research.

Language: Английский

Citations

118
Broadly neutralizing anti-S2 antibodies protect against all three human betacoronaviruses that cause deadly disease DOI Creative Commons
Pan-Pan Zhou, Ge Song,

Hejun Liu

et al.

Immunity, Journal Year: 2023, Volume and Issue: 56(3), P. 669 - 686.e7

Published: Feb. 16, 2023

Pan-betacoronavirus neutralizing antibodies may hold the key to developing broadly protective vaccines against novel pandemic coronaviruses and more effectively respond SARS-CoV-2 variants. The emergence of Omicron subvariants illustrates limitations solely targeting receptor-binding domain (RBD) spike (S) protein. Here, we isolated a large panel (bnAbs) from recovered-vaccinated donors, which targets conserved S2 region in betacoronavirus fusion machinery. Select bnAbs showed broad vivo protection all three deadly betacoronaviruses, SARS-CoV-1, SARS-CoV-2, MERS-CoV, have spilled over into humans past two decades. Structural studies these delineated molecular basis for their reactivity revealed common antibody features targetable by vaccination strategies. These provide new insights opportunities antibody-based interventions pan-betacoronavirus vaccines.

Language: Английский

Citations

118