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.
| Authors | Rawle, Daniel J; Le, Thuy T; Dumenil, Troy; Yan, Kexin; Tang, Bing; Nguyen, Wilson; Watterson, Daniel; Modhiran, Naphak; Hobson-Peters, Jody; Bishop, Cameron; Suhrbier, Andreas |
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| Journal | PLOS PATHOGENS |
| Pages | e1009723 |
| Volume | 17 |
| Date | 1/01/2021 |
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| URL | http://www.ncbi.nlm.nih.gov/pubmed/?term=10.1371/journal.ppat.1009723 |