Loss of furin cleavage site attenuates SARS-CoV-2 pathogenesis
- 25 January 2021
- journal article
- research article
- Published by Springer Science and Business Media LLC in Nature
- Vol. 591 (7849), 293-299
- https://doi.org/10.1038/s41586-021-03237-4
Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)—a new coronavirus that has led to a worldwide pandemic1—has a furin cleavage site (PRRAR) in its spike protein that is absent in other group-2B coronaviruses2. To explore whether the furin cleavage site contributes to infection and pathogenesis in this virus, we generated a mutant SARS-CoV-2 that lacks the furin cleavage site (ΔPRRA). Here we report that replicates of ΔPRRA SARS-CoV-2 had faster kinetics, improved fitness in Vero E6 cells and reduced spike protein processing, as compared to parental SARS-CoV-2. However, the ΔPRRA mutant had reduced replication in a human respiratory cell line and was attenuated in both hamster and K18-hACE2 transgenic mouse models of SARS-CoV-2 pathogenesis. Despite reduced disease, the ΔPRRA mutant conferred protection against rechallenge with the parental SARS-CoV-2. Importantly, the neutralization values of sera from patients with coronavirus disease 2019 (COVID-19) and monoclonal antibodies against the receptor-binding domain of SARS-CoV-2 were lower against the ΔPRRA mutant than against parental SARS-CoV-2, probably owing to an increased ratio of particles to plaque-forming units in infections with the former. Together, our results demonstrate a critical role for the furin cleavage site in infection with SARS-CoV-2 and highlight the importance of this site for evaluating the neutralization activities of antibodies.Keywords
This publication has 48 references indexed in Scilit:
- Mechanisms of Severe Acute Respiratory Syndrome Coronavirus-Induced Acute Lung InjurymBio, 2013
- Cell Host Response to Infection with Novel Human Coronavirus EMC Predicts Potential Antivirals and Important Differences with SARS CoronavirusmBio, 2013
- Evaluation of Respiratory System Mechanics in Mice using the Forced Oscillation TechniqueJournal of Visualized Experiments, 2013
- Release of Severe Acute Respiratory Syndrome Coronavirus Nuclear Import Block Enhances Host Transcription in Human Lung CellsJournal of Virology, 2013
- BEDTools: a flexible suite of utilities for comparing genomic featuresBioinformatics, 2010
- The Sequence Alignment/Map format and SAMtoolsBioinformatics, 2009
- PAnnBuilder: an R package for assembling proteomic annotation dataBioinformatics, 2009
- Pathways of Cross-Species Transmission of Synthetically Reconstructed Zoonotic Severe Acute Respiratory Syndrome CoronavirusJournal of Virology, 2008
- A Mouse-Adapted SARS-Coronavirus Causes Disease and Mortality in BALB/c MicePLoS Pathogens, 2007
- Proprotein and prohormone convertases: a family of subtilases generating diverse bioactive polypeptides1Published on the World Wide Web on 17 August 1999.1Brain Research, 1999