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ACE2-lentiviral transduction enables mouse SARS-CoV-2 infection and mapping of receptor interactions
- Source :
- PLoS Pathogens, PLoS Pathogens, Vol 17, Iss 7, p e1009723 (2021)
- Publication Year :
- 2021
- Publisher :
- Public Library of Science (PLoS), 2021.
-
Abstract
- SARS-CoV-2 uses the human ACE2 (hACE2) receptor for cell attachment and entry, with mouse ACE2 (mACE2) unable to support infection. Herein we describe an ACE2-lentivirus system and illustrate its utility for in vitro and in vivo SARS-CoV-2 infection models. Transduction of non-permissive cell lines with hACE2 imparted replication competence, and transduction with mACE2 containing N30D, N31K, F83Y and H353K substitutions, to match hACE2, rescued SARS-CoV-2 replication. Intrapulmonary hACE2-lentivirus transduction of C57BL/6J mice permitted significant virus replication in lung epithelium. RNA-Seq and histological analyses illustrated that this model involved an acute inflammatory disease followed by resolution and tissue repair, with a transcriptomic profile similar to that seen in COVID-19 patients. hACE2-lentivirus transduction of IFNAR-/- and IL-28RA-/- mouse lungs was used to illustrate that loss of type I or III interferon responses have no significant effect on virus replication. However, their importance in driving inflammatory responses was illustrated by RNA-Seq analyses. We also demonstrate the utility of the hACE2-lentivirus transduction system for vaccine evaluation in C57BL/6J mice. The ACE2-lentivirus system thus has broad application in SARS-CoV-2 research, providing a tool for both mutagenesis studies and mouse model development.<br />Author summary SARS-CoV-2 uses the human ACE2 (hACE2) receptor to infect cells, but cannot infect mice because the virus cannot bind mouse ACE2 (mACE2). We use an ACE2-lentivirus system in vitro to identify four key amino acids in mACE2 that explain why SARS-CoV-2 cannot infect mice. hACE2-lentivirus was used to express hACE2 in mouse lungs in vivo, with the inflammatory responses after SARS-CoV-2 infection similar to those seen in human COVID-19. Genetically modified mice were used to show that type I and III interferon signaling is required for the inflammatory responses. We also show that the hACE2-lentivirus mouse model can be used to test vaccines. Overall this paper demonstrates that our hACE2-lentivirus system has multiple applications in SARS-CoV-2 and COVID-19 research.
- Subjects :
- RNA viruses
Viral Diseases
Vaccine evaluation
Coronaviruses
viruses
Respiratory System
Mice
Transduction (genetics)
Medical Conditions
0302 clinical medicine
Transduction, Genetic
Interferon
Chlorocebus aethiops
Biology (General)
Receptor
Immune Response
Pathology and laboratory medicine
Mice, Knockout
0303 health sciences
Animal Models
Medical microbiology
Cell biology
Infectious Diseases
Experimental Organism Systems
Viruses
Angiotensin-Converting Enzyme 2
SARS CoV 2
Pathogens
Anatomy
Research Article
medicine.drug
SARS coronavirus
QH301-705.5
Immunology
Mutagenesis (molecular biology technique)
Mouse Models
Biology
Research and Analysis Methods
Microbiology
03 medical and health sciences
Model Organisms
Signs and Symptoms
Virology
Retroviruses
Genetics
medicine
Animals
Humans
Animal Models of Disease
Bronchioles
Vero Cells
Molecular Biology
030304 developmental biology
Medicine and health sciences
Inflammation
Biology and life sciences
SARS-CoV-2
Gene Expression Profiling
Lentivirus
Organisms
Viral pathogens
COVID-19
Covid 19
RC581-607
Viral Replication
Microbial pathogens
Animal Models of Infection
Disease Models, Animal
Viral replication
Cell culture
Animal Studies
Vero cell
Parasitology
Immunologic diseases. Allergy
Clinical Medicine
030217 neurology & neurosurgery
Subjects
Details
- ISSN :
- 15537374
- Volume :
- 17
- Database :
- OpenAIRE
- Journal :
- PLOS Pathogens
- Accession number :
- edsair.doi.dedup.....bf064db08532229613add382edf0d01a