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Detection of SARS-CoV-2 Neutralizing Antibodies using High-Throughput Fluorescent Imaging of Pseudovirus Infection
Published on: June 5, 2021
The Apolipoprotein E neutralizing antibody inhibits SARS-CoV-2 infection by blocking cellular entry of lipoviral
Qi Cui1, Arjit Vijey Jeyachandran2, Gustavo Garcia2
1Department of Neurodegenerative Diseases Beckman Research Institute of City of Hope Duarte California USA.
Abstract:
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causal agent for coronavirus disease 2019 (COVID-19). Although vaccines have helped to prevent uncontrolled viral spreading, our understanding of the fundamental biology of SARS-CoV-2 infection remains insufficient, which hinders effective therapeutic development. Here, we found that Apolipoprotein E (ApoE), a lipid binding protein, is hijacked by SARS-CoV-2 for infection. Preincubation of SARS-CoV-2 with a neutralizing antibody specific to ApoE led to inhibition of SARS-CoV-2 infection. The ApoE neutralizing antibody efficiently blocked SARS-CoV-2 infection of human iPSC-derived astrocytes and air-liquid interface organoid models in addition to human ACE2-expressing HEK293T cells and Calu-3 lung cells. ApoE mediates SARS-CoV-2 entry through binding to its cellular receptors such as the low density lipoprotein receptor (LDLR). LDLR knockout or ApoE mutations at the receptor binding domain or an ApoE mimetic peptide reduced SARS-CoV-2 infection. Furthermore, we detected strong membrane LDLR expression on SARS-CoV-2 Spike-positive cells in human lung tissues, whereas no or low ACE2 expression was detected. This study provides a new paradigm for SARS-CoV-2 cellular entry through binding of ApoE on the lipoviral particles to host cell receptor(s). Moreover, this study suggests that ApoE neutralizing antibodies are promising antiviral therapies for COVID-19 by blocking entry of both parental virus and variants of concern.
Insights
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) hijacks Apolipoprotein E (ApoE) for infection. ApoE-neutralizing antibodies effectively block SARS-CoV-2 entry, offering a promising therapeutic strategy for COVID-19 and its variants.
Area of Science:
- Virology
- Immunology
- Cell Biology
Background:
- Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes COVID-19, but its infection biology requires further elucidation for therapeutic development.
- Current understanding of SARS-CoV-2 infection mechanisms is insufficient for effective treatment strategies.
Purpose of the Study:
- To investigate the role of Apolipoprotein E (ApoE) in SARS-CoV-2 infection.
- To explore ApoE-neutralizing antibodies as a potential antiviral therapy against SARS-CoV-2.
Main Methods:
- Preincubation of SARS-CoV-2 with ApoE-specific neutralizing antibodies.
- Assessing viral infection in various cell models (HEK293T, Calu-3, iPSC-derived astrocytes, ALI organoids).
- Investigating the role of low-density lipoprotein receptor (LDLR) and ApoE mutations in viral entry.
Main Results:
- Apolipoprotein E (ApoE) is hijacked by SARS-CoV-2 for cellular entry.
- ApoE-neutralizing antibodies significantly inhibited SARS-CoV-2 infection across multiple cell types and organoid models.
- ApoE mediates viral entry via cellular receptors like LDLR; LDLR knockout and ApoE mutations reduced infection.
- High LDLR expression was observed on SARS-CoV-2-infected lung cells, with low ACE2 expression.
Conclusions:
- SARS-CoV-2 utilizes ApoE for cellular entry, binding to host receptors like LDLR.
- ApoE-neutralizing antibodies represent a promising therapeutic approach for blocking SARS-CoV-2 entry, including variants.
- This discovery offers a new paradigm for understanding SARS-CoV-2 infection and developing novel antiviral treatments.
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