Effect of SARS-CoV-2 spike mutations on animal ACE2 usage and in vitro neutralization sensitivity

Yao, Weitong; Ma, Danting; Wang, Haimin; Tang, Xiaojuan; Du, Chen; Pan, Hong; Li, Chao; Lin, Hua; Farzan, Michael; Zhao, Jincun; Li, Yujun; Zhong, Guocai

doi:10.1101/2021.01.27.428353

Cited by 32 publications

(27 citation statements)

References 69 publications

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“…While it has been shown that mutations result in more fit, and likely more contagious viruses (15,16,40), the serological consequences of the mutations found in VOC are unclear (40). Recent studies have shown reduced binding to therapeutic antibodies or Spike-specific antibodies for the circulating VOC B.1.1.7, 501Y.V2 and P.1 in vitro (41,42). All three VOC harbor an N501Y mutation within S-RBD, while the 501Y.V2 and P.1 variants contain two additional RBD changes, K417N/T and E484K.…”

Section: Discussionmentioning

confidence: 99%

Epitope-specific antibody responses differentiate COVID-19 outcomes and variants of concern

Voss¹,

Esmail²,

Liu³

et al. 2021

JCI Insight

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BACKGROUND. The role of humoral immunity in the coronavirus disease 2019 (COVID-19) is not fully understood owing, in large part, to the complexity of antibodies produced in response to the SARS-CoV-2 infection. There is a pressing need for serology tests to assess patient-specific antibody response and predict clinical outcome. METHODS. Using SARS-CoV-2 proteome and peptide microarrays, we screened 146 COVID-19 patients plasma samples to identify antigens and epitopes. This enabled us to develop a master epitope array and an epitope-specific agglutination assay to gauge antibody responses systematically and with high resolution. RESULTS. We identified linear epitopes from the Spike (S) and Nucleocapsid (N) protein and showed that the epitopes enabled higher resolution antibody profiling than the S or N protein antigen. Specifically, we found that antibody responses to the S(811-825), S(881-895) and N(156-170) epitopes negatively or positively correlated with clinical severity or patient survival. Moreover, we found that the P681H and S235F mutations associated with the coronavirus variant of concern B.1.1.7 altered the specificity of the corresponding epitopes. CONCLUSIONS. Epitope-resolved antibody testing not only affords a high-resolution alternativeto conventional immunoassays to delineate the complex humoral immunity to SARS-CoV-2 and differentiate between neutralizing and non-neutralizing antibodies, it may potentially be used to predict clinical outcome. The epitope peptides can be readily modified to detect antibodies against variants of concern (VOC) in both the peptide array and latex agglutination formats.

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Section: Discussionmentioning

confidence: 99%

Epitope-specific antibody responses differentiate COVID-19 outcomes and variants of concern

Voss¹,

Esmail²,

Liu³

et al. 2021

JCI Insight

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“…Finally, it might be possible to extend our data into the increased ACE2 receptor binding affinities of circulating variant viruses 35–37 . A hypothesis would be that these viruses can infect the upper respiratory tract, in which ACE2 is scarce, more efficiently leading to increased transmission, a highly similar model as observed for human influenza A viruses 38,39 .…”

Section: Discussionmentioning

confidence: 93%

3D visualization of SARS-CoV-2 infection and receptor distribution in Syrian hamster lung lobes display distinct spatial arrangements

Tomris

Bouwman

Adolfs

et al. 2021

Preprint

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SARS-CoV-2 attaches to angiotensin-converting enzyme 2 (ACE2) to gain entry into cells after which the spike protein is cleaved by the transmembrane serine protease 2 (TMPRRS2) to facilitate viral-host membrane fusion. ACE2 and TMPRRS2 expression profiles have been analyzed at the genomic, transcriptomic, and single-cell RNAseq level, however, biologically relevant protein receptor organization in whole tissues is still poorly understood. To describe the organ-level architecture of receptor expression, related to the ability of ACE2 and TMPRRS2 to mediate infectivity, we performed a volumetric analysis of whole Syrian hamster lung lobes. Lung tissue of infected and control animals were stained using antibodies against ACE2 and TMPRRS2, combined with fluorescent spike protein and SARS-CoV-2 nucleoprotein staining. This was followed by light-sheet microscopy imaging to visualize expression patterns. The data demonstrates that infection is restricted to sites with both ACE2 and TMPRRS2, the latter is expressed in the primary and secondary bronchi whereas ACE2 is predominantly observed in the terminal bronchioles and alveoli. Conversely, infection completely overlaps at these sites where ACE2 and TMPRSS2 co-localize.

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“…55,56 Moreover, neutralizing monoclonal antibody therapies may have reduced effects on some naturally existing SARS-CoV-2 variants. 57 For example, while B.1.1.7 variant normally did not influence antibody neutralizing ability, B.1.351 and P.1 variants were partially resistant to casirivimab and completely resistant to bamlanivimab in vitro. 41,[57][58][59] In light of the markedly increasing spread of SARS-CoV-2 variants potentially resistant to bamlanivimab, the US government has halted distribution of bamlanivimab monotherapy on 24 March 2021, and the US FDA retracted the EUA of bamlanivimab monotherapy on 16 April 2021.…”

Section: Neutralizing Monoclonal Antibodiesmentioning

confidence: 97%

“…57 For example, while B.1.1.7 variant normally did not influence antibody neutralizing ability, B.1.351 and P.1 variants were partially resistant to casirivimab and completely resistant to bamlanivimab in vitro. 41,[57][58][59] In light of the markedly increasing spread of SARS-CoV-2 variants potentially resistant to bamlanivimab, the US government has halted distribution of bamlanivimab monotherapy on 24 March 2021, and the US FDA retracted the EUA of bamlanivimab monotherapy on 16 April 2021. 60,61 The combination use of two or more potent monoclonal antibodies targeting noncompeting sites on SARS-CoV-2 may reduce the possibility of virus resistance and mutational escape.…”

Section: Neutralizing Monoclonal Antibodiesmentioning

confidence: 97%

Contemporary narrative review of treatment options for COVID‐19

2021

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The coronavirus disease 2019 (COVID-19) pandemic is ongoing and many drugs have been studied in clinical trials. From a pathophysiological perspective, anti-viral drugs may be more effective in the early stage while immunomodulators may be more effective in severe patients in later stages of infection. While drugs such as lopinavirritonavir, hydroxychloroquine and azithromycin have proved to be ineffective in randomized controlled trials, corticosteroids, neutralizing monoclonal antibodies, remdesivir, tocilizumab and baricitinib have been reported to benefit certain groups of patients with COVID-19. In this review, we will present the key clinical evidence and progress in promising COVID-19 therapeutics, as well as summarize the experience and lessons learned from the development of the current therapeutics.

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Effect of SARS-CoV-2 spike mutations on animal ACE2 usage and in vitro neutralization sensitivity

Cited by 32 publications

References 69 publications

Epitope-specific antibody responses differentiate COVID-19 outcomes and variants of concern

Epitope-specific antibody responses differentiate COVID-19 outcomes and variants of concern

3D visualization of SARS-CoV-2 infection and receptor distribution in Syrian hamster lung lobes display distinct spatial arrangements

Contemporary narrative review of treatment options for COVID‐19

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