A protease-activatable luminescent biosensor and reporter cell line for authentic SARS-CoV-2 infection

Efforts to define serological correlates of protection against COVID-19 have been hampered by the lack of a simple, scalable, standardised assay for SARS-CoV-2 infection and antibody neutralisation. Plaque assays remain the gold standard, but are impractical for high-throughput screening. In this st...

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Published inPLoS pathogens Vol. 18; no. 2; p. e1010265
Main Authors Gerber, Pehuén Pereyra, Duncan, Lidia M., Greenwood, Edward JD, Marelli, Sara, Naamati, Adi, Teixeira-Silva, Ana, Crozier, Thomas WM, Gabaev, Ildar, Zhan, Jun R., Mulroney, Thomas E., Horner, Emily C., Doffinger, Rainer, Willis, Anne E., Thaventhiran, James ED, Protasio, Anna V., Matheson, Nicholas J.
Format Journal Article
LanguageEnglish
Published United States Public Library of Science 10.02.2022
Public Library of Science (PLoS)
Subjects
Antibodies
Assaying
Biology and life sciences
Biosensing Techniques - methods
Biosensors
Cell activation
Cell Line
Coronaviruses
COVID-19
COVID-19 - diagnosis
COVID-19 - virology
COVID-19 Testing - methods
Engineering and Technology
Experiments
Flow cytometry
Health aspects
High-throughput screening
HIV
Human immunodeficiency virus
Humans
Infections
Luminescent Measurements - methods
Medicine and health sciences
Microscopy
Peptide Hydrolases - analysis
Peptide Hydrolases - genetics
Peptide Hydrolases - metabolism
Physical Sciences
Physiological aspects
Protease
Proteases
Proteinase
Proteins
Quantitation
Research and Analysis Methods
SARS-CoV-2 - enzymology
SARS-CoV-2 - genetics
SARS-CoV-2 - physiology
Severe acute respiratory syndrome
Severe acute respiratory syndrome coronavirus 2
Titration
Viral diseases
Viral infections
Viral Proteins - analysis
Viral Proteins - genetics
Viral Proteins - metabolism
Virus Replication
Viruses
United Kingdom
Online AccessGet full text
ISSN1553-7374
1553-7366
1553-7374
DOI10.1371/journal.ppat.1010265

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Abstract Efforts to define serological correlates of protection against COVID-19 have been hampered by the lack of a simple, scalable, standardised assay for SARS-CoV-2 infection and antibody neutralisation. Plaque assays remain the gold standard, but are impractical for high-throughput screening. In this study, we show that expression of viral proteases may be used to quantitate infected cells. Our assays exploit the cleavage of specific oligopeptide linkers, leading to the activation of cell-based optical biosensors. First, we characterise these biosensors using recombinant SARS-CoV-2 proteases. Next, we confirm their ability to detect viral protease expression during replication of authentic virus. Finally, we generate reporter cells stably expressing an optimised luciferase-based biosensor, enabling viral infection to be measured within 24 h in a 96- or 384-well plate format, including variants of concern. We have therefore developed a luminescent SARS-CoV-2 reporter cell line, and demonstrated its utility for the relative quantitation of infectious virus and titration of neutralising antibodies.
AbstractList Efforts to define serological correlates of protection against COVID-19 have been hampered by the lack of a simple, scalable, standardised assay for SARS-CoV-2 infection and antibody neutralisation. Plaque assays remain the gold standard, but are impractical for high-throughput screening. In this study, we show that expression of viral proteases may be used to quantitate infected cells. Our assays exploit the cleavage of specific oligopeptide linkers, leading to the activation of cell-based optical biosensors. First, we characterise these biosensors using recombinant SARS-CoV-2 proteases. Next, we confirm their ability to detect viral protease expression during replication of authentic virus. Finally, we generate reporter cells stably expressing an optimised luciferase-based biosensor, enabling viral infection to be measured within 24 h in a 96- or 384-well plate format, including variants of concern. We have therefore developed a luminescent SARS-CoV-2 reporter cell line, and demonstrated its utility for the relative quantitation of infectious virus and titration of neutralising antibodies. Techniques for measuring infection with SARS-CoV-2 in the laboratory are laborious and time-consuming, and different laboratories use different approaches. There is therefore no generally agreed way to quantitate neutralising antibodies against SARS-CoV-2, which block infection with the virus and protect people from COVID-19. In this study, we describe a new way to measure SARS-CoV-2 infection, which is much simpler and faster than existing methods. It relies on the production of a specific protease enzyme by the virus, which is able to cleave and activate an engineered protein biosensor in infected cells. This biosensor emits light in the presence of viral infection, and the amount of light released is used as a readout for the amount of infectious SARS-CoV-2 present. The signal is very sensitive, so the number of infected cells required is very small, and the method can be scaled-up to test many samples at once. In particular, we demonstrate how it can be used to detect different variants of SARS-CoV-2, and quantitate neutralising antibodies against these viruses.
Efforts to define serological correlates of protection against COVID-19 have been hampered by the lack of a simple, scalable, standardised assay for SARS-CoV-2 infection and antibody neutralisation. Plaque assays remain the gold standard, but are impractical for high-throughput screening. In this study, we show that expression of viral proteases may be used to quantitate infected cells. Our assays exploit the cleavage of specific oligopeptide linkers, leading to the activation of cell-based optical biosensors. First, we characterise these biosensors using recombinant SARS-CoV-2 proteases. Next, we confirm their ability to detect viral protease expression during replication of authentic virus. Finally, we generate reporter cells stably expressing an optimised luciferase-based biosensor, enabling viral infection to be measured within 24 h in a 96- or 384-well plate format, including variants of concern. We have therefore developed a luminescent SARS-CoV-2 reporter cell line, and demonstrated its utility for the relative quantitation of infectious virus and titration of neutralising antibodies.Efforts to define serological correlates of protection against COVID-19 have been hampered by the lack of a simple, scalable, standardised assay for SARS-CoV-2 infection and antibody neutralisation. Plaque assays remain the gold standard, but are impractical for high-throughput screening. In this study, we show that expression of viral proteases may be used to quantitate infected cells. Our assays exploit the cleavage of specific oligopeptide linkers, leading to the activation of cell-based optical biosensors. First, we characterise these biosensors using recombinant SARS-CoV-2 proteases. Next, we confirm their ability to detect viral protease expression during replication of authentic virus. Finally, we generate reporter cells stably expressing an optimised luciferase-based biosensor, enabling viral infection to be measured within 24 h in a 96- or 384-well plate format, including variants of concern. We have therefore developed a luminescent SARS-CoV-2 reporter cell line, and demonstrated its utility for the relative quantitation of infectious virus and titration of neutralising antibodies.
Efforts to define serological correlates of protection against COVID-19 have been hampered by the lack of a simple, scalable, standardised assay for SARS-CoV-2 infection and antibody neutralisation. Plaque assays remain the gold standard, but are impractical for high-throughput screening. In this study, we show that expression of viral proteases may be used to quantitate infected cells. Our assays exploit the cleavage of specific oligopeptide linkers, leading to the activation of cell-based optical biosensors. First, we characterise these biosensors using recombinant SARS-CoV-2 proteases. Next, we confirm their ability to detect viral protease expression during replication of authentic virus. Finally, we generate reporter cells stably expressing an optimised luciferase-based biosensor, enabling viral infection to be measured within 24 h in a 96- or 384-well plate format, including variants of concern. We have therefore developed a luminescent SARS-CoV-2 reporter cell line, and demonstrated its utility for the relative quantitation of infectious virus and titration of neutralising antibodies.
Audience Academic
Author Gabaev, Ildar
Horner, Emily C.
Marelli, Sara
Matheson, Nicholas J.
Duncan, Lidia M.
Willis, Anne E.
Crozier, Thomas WM
Teixeira-Silva, Ana
Gerber, Pehuén Pereyra
Zhan, Jun R.
Naamati, Adi
Protasio, Anna V.
Greenwood, Edward JD
Doffinger, Rainer
Thaventhiran, James ED
Mulroney, Thomas E.
AuthorAffiliation Emory University, UNITED STATES
1 Department of Medicine, University of Cambridge, Cambridge, United Kingdom
5 Department of Pathology, University of Cambridge, Cambridge, United Kingdom
6 NHS Blood and Transplant, Cambridge, United Kingdom
4 Department of Clinical Biochemistry and Immunology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, United Kingdom
2 Cambridge Institute for Therapeutic Immunology and Infectious Disease (CITIID), Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge, United Kingdom
3 MRC Toxicology Unit, University of Cambridge, Cambridge, United Kingdom
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BackLink https://www.ncbi.nlm.nih.gov/pubmed/35143592$$D View this record in MEDLINE/PubMed
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2022 Gerber et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.
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PublicationDate_xml – month: 2
  year: 2022
  text: 20220210
  day: 10
PublicationDecade 2020
PublicationPlace United States
PublicationPlace_xml – name: United States
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– name: San Francisco, CA USA
PublicationTitle PLoS pathogens
PublicationTitleAlternate PLoS Pathog
PublicationYear 2022
Publisher Public Library of Science
Public Library of Science (PLoS)
Publisher_xml – name: Public Library of Science
– name: Public Library of Science (PLoS)
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Snippet Efforts to define serological correlates of protection against COVID-19 have been hampered by the lack of a simple, scalable, standardised assay for SARS-CoV-2...
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SubjectTerms Antibodies
Assaying
Biology and life sciences
Biosensing Techniques - methods
Biosensors
Cell activation
Cell Line
Coronaviruses
COVID-19
COVID-19 - diagnosis
COVID-19 - virology
COVID-19 Testing - methods
Engineering and Technology
Experiments
Flow cytometry
Health aspects
High-throughput screening
HIV
Human immunodeficiency virus
Humans
Infections
Luminescent Measurements - methods
Medicine and health sciences
Microscopy
Peptide Hydrolases - analysis
Peptide Hydrolases - genetics
Peptide Hydrolases - metabolism
Physical Sciences
Physiological aspects
Protease
Proteases
Proteinase
Proteins
Quantitation
Research and Analysis Methods
SARS-CoV-2 - enzymology
SARS-CoV-2 - genetics
SARS-CoV-2 - physiology
Severe acute respiratory syndrome
Severe acute respiratory syndrome coronavirus 2
Titration
Viral diseases
Viral infections
Viral Proteins - analysis
Viral Proteins - genetics
Viral Proteins - metabolism
Virus Replication
Viruses
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Title A protease-activatable luminescent biosensor and reporter cell line for authentic SARS-CoV-2 infection
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