ACE2-lentiviral transduction enables mouse SARS-CoV-2 infection and mapping of receptor interactions

• Published in: PLoS pathogens 2021-07, Vol.17 (7), p.e1009723
• Main 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
• Format: Article
• Language: English
• Subjects: ACE2; Amino acids; Angiotensin-converting enzyme 2; Animal models; Biology and life sciences; Cell adhesion; Cell culture; Cell lines; Cell receptors; Coronaviruses; COVID-19; COVID-19 vaccines; Cystic fibrosis; Epithelium; Flow cytometry; Gene expression; Health aspects; Host-virus relationships; Infections; Inflammatory diseases; Interferon; Kinases; Lungs; Medical research; Medicine and health sciences; Mutagenesis; Pandemics; Receptors; Replication; Research and Analysis Methods; Severe acute respiratory syndrome; Severe acute respiratory syndrome coronavirus 2; Transcriptomics; Transduction; Vaccines; Viral diseases; Viruses
• ISSN: 1553-7374; 1553-7366; 1553-7374
• DOI: 10.1371/journal.ppat.1009723

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.