TY - JOUR
T1 - SARS-CoV-2 Causes Lung Infection without Severe Disease in Human ACE2 Knock-In Mice
AU - Winkler, Emma S.
AU - Chen, Rita E.
AU - Alam, Fahmida
AU - Yildiz, Soner
AU - Case, James Brett
AU - Uccellini, Melissa B.
AU - Holtzman, Michael J.
AU - Garcia-Sastre, Adolfo
AU - Schotsaert, Michael
AU - Diamond, Michael S.
N1 - Funding Information:
This study was supported by the NIH (R01 AI157155, R35-HL145242, and R01 AI130591) and the Defense Advanced Research Project Agency (HR001117S0019 and HR0011-507 19-2-0020). This study was also partly funded by CRIPT (Center for Research on Influenza Pathogenesis and Transmission), a NIAID-funded Center of Excellence for Influenza Research and Response (CEIRR, contract 75N93021C00014), by a Fast Grant of the Mercatus Center, and by the generous support of the JPB Foundation, the Open Philanthropy Project (research grant 2020-215611 [5384]), and anonymous donors to A.G.-S. E.S.W. is supported by F30 AI152327. J.B.C. is supported by a Helen Hay Whitney Foundation postdoctoral fellowship. S.Y. received funding from Swiss National Foundation (SNF) Postdoc Mobility fellowship (P400PB_199292). M.J.H. is supported by the Department of Defense (PR190726), the Cystic Fibrosis Foundation, Bebermeyer Fund, Hardy Trust, and Schaefer Fund.
Publisher Copyright:
© 2022 American Society for Microbiology.
PY - 2022/1
Y1 - 2022/1
N2 - The development of mouse models for coronavirus disease 2019 (COVID- 19) has enabled testing of vaccines and therapeutics and defining aspects of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pathogenesis. SARS-CoV-2 disease is severe in K18 transgenic mice (K18-hACE2 Tg) expressing human angiotensin-converting enzyme 2 (hACE2), the SARS-CoV-2 receptor, under an ectopic cytokeratin promoter, with high levels of infection measured in the lung and brain. Here, we evaluated SARSCoV- 2 infection in hACE2 knock-in (KI) mice that express hACE2 under an endogenous promoter in place of murine ACE2 (mACE2). Intranasal inoculation of hACE2 KI mice with SARS-CoV-2 WA1/2020 resulted in substantial viral replication within the upper and lower respiratory tracts with limited spread to extrapulmonary organs. However, SARS-CoV-2- infected hACE2 KI mice did not lose weight and developed limited pathology. Moreover, no significant differences in viral burden were observed in hACE2 KI mice infected with B.1.1.7 or B.1.351 variants compared to the WA1/2020 strain. Because the entry mechanisms of SARS-CoV-2 in mice remain uncertain, we evaluated the impact of the naturally occurring, mouse-adapting N501Y mutation by comparing infection of hACE2 KI, K18- hACE2 Tg, ACE2-deficient, and wild-type C57BL/6 mice. The N501Y mutation minimally affected SARS-CoV-2 infection in hACE2 KI mice but was required for viral replication in wild-type C57BL/6 mice in a mACE2-dependent manner and augmented pathogenesis in the K18-hACE2 Tg mice. Thus, the N501Y mutation likely enhances interactions with mACE2 or hACE2 in vivo. Overall, our study highlights the hACE2 KI mice as a model of mild SARS-CoV-2 infection and disease and clarifies the requirement of the N501Y mutation in mice.
AB - The development of mouse models for coronavirus disease 2019 (COVID- 19) has enabled testing of vaccines and therapeutics and defining aspects of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pathogenesis. SARS-CoV-2 disease is severe in K18 transgenic mice (K18-hACE2 Tg) expressing human angiotensin-converting enzyme 2 (hACE2), the SARS-CoV-2 receptor, under an ectopic cytokeratin promoter, with high levels of infection measured in the lung and brain. Here, we evaluated SARSCoV- 2 infection in hACE2 knock-in (KI) mice that express hACE2 under an endogenous promoter in place of murine ACE2 (mACE2). Intranasal inoculation of hACE2 KI mice with SARS-CoV-2 WA1/2020 resulted in substantial viral replication within the upper and lower respiratory tracts with limited spread to extrapulmonary organs. However, SARS-CoV-2- infected hACE2 KI mice did not lose weight and developed limited pathology. Moreover, no significant differences in viral burden were observed in hACE2 KI mice infected with B.1.1.7 or B.1.351 variants compared to the WA1/2020 strain. Because the entry mechanisms of SARS-CoV-2 in mice remain uncertain, we evaluated the impact of the naturally occurring, mouse-adapting N501Y mutation by comparing infection of hACE2 KI, K18- hACE2 Tg, ACE2-deficient, and wild-type C57BL/6 mice. The N501Y mutation minimally affected SARS-CoV-2 infection in hACE2 KI mice but was required for viral replication in wild-type C57BL/6 mice in a mACE2-dependent manner and augmented pathogenesis in the K18-hACE2 Tg mice. Thus, the N501Y mutation likely enhances interactions with mACE2 or hACE2 in vivo. Overall, our study highlights the hACE2 KI mice as a model of mild SARS-CoV-2 infection and disease and clarifies the requirement of the N501Y mutation in mice.
KW - Lung infection
KW - Mouse model
KW - Pathogenesis
KW - SARS-CoV-2
UR - http://www.scopus.com/inward/record.url?scp=85123050058&partnerID=8YFLogxK
U2 - 10.1128/JVI.01511-21
DO - 10.1128/JVI.01511-21
M3 - Article
C2 - 34668780
AN - SCOPUS:85123050058
SN - 0022-538X
VL - 96
JO - Journal of Virology
JF - Journal of Virology
IS - 1
M1 - e01511-21
ER -