Lung Expression of Human Angiotensin-Converting Enzyme 2 Sensitizes the Mouse to SARS-CoV-2 Infection

被引：39

作者：

Han, Kun ^{[1
]}

Blair, Robert, V ^{[1
]}

Iwanaga, Naoki ^{[2
,3
]}

Liu, Fengming ^{[1
,4
]}

Russell-Lodrigue, Kasi E. ^{[1
]}

Qin, Zhongnan ^{[1
,4
]}

Midkiff, Cecily C. ^{[1
]}

Golden, Nadia A. ^{[1
]}

Doyle-Meyers, Lara A. ^{[1
]}

Kabir, Mohammad E. ^{[1
,4
]}

Chandler, Kristin E. ^{[1
]}

Cutrera, Kellie L. ^{[1
]}

Ren, Mi ^{[1
,4
]}

Monjure, Christopher J. ^{[1
]}

Lehmicke, Gabrielle ^{[1
,4
]}

Fischer, Tracy ^{[1
,4
]}

Beddingfield, Brandon ^{[1
]}

Wanek, Alanna G. ^{[2
,3
]}

Birnbaum, Angela ^{[1
]}

Maness, Nicholas J. ^{[1
,4
]}

Roy, Chad J. ^{[1
,4
]}

Datta, Prasun K. ^{[1
,4
]}

Rappaport, Jay ^{[1
,4
]}

Kolls, Jay K. ^{[2
,3
]}

Qin, Xuebin ^{[1
,4
]}

机构：

[1] Tulane Natl Primate Res Ctr, Covington, LA 70433 USA

[2] Tulane Univ, Sch Med, Dept Med, Ctr Translat Res Infect & Inflammat, New Orleans, LA 70112 USA

[3] Tulane Univ, Sch Med, Dept Pediat, Ctr Translat Res Infect & Inflammat, New Orleans, LA 70112 USA

[4] Tulane Univ, Sch Med, Dept Immunol & Microbiol, 1430 Tulane Ave, New Orleans, LA 70112 USA

来源：

AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY | 2021年 / 64卷 / 01期

基金：

美国国家卫生研究院;

关键词：

SARS-CoV-2; COVID-19; human ACE2; immune responses; mouse model; HUMAN CD59; ABLATION; SPIKE; ACE2; MICE;

D O I：

10.1165/rcmb.2020-0354OC

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Preclinical mouse models that recapitulate some characteristics of coronavirus disease (COVID-19) will facilitate focused study of pathogenesis and virus-host responses. Human agniotensin-converting enzyme 2 (hACE2) serves as an entry receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) to infect people via binding to envelope spike proteins. Herein we report development and characterization of a rapidly deployable COVID-19 mouse model. C57BL/6J (B6) mice expressing hACE2 in the lung were transduced by oropharyngeal delivery of the recombinant human adenovirus type 5 that expresses hACE2 (Ad5-hACE2). Mice were infected with SARS-CoV-2 at Day 4 after transduction and developed interstitial pneumonia associated with perivascular inflammation, accompanied by significantly higher viral load in lungs at Days 3, 6, and 12 after infection compared with Ad5-empty control group. SARS-CoV-2 was detected in pneumocytes in alveolar septa. Transcriptomic analysis of lungs demonstrated that the infected Ad5-hACE mice had a significant increase in IFN-dependent chemokines Cxcl9 and Cxcl10, and genes associated with effector T-cell populations including Cd3 g, Cd8a, and Gzmb. Pathway analysis showed that several Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways were enriched in the data set, including cytokine-cytokine receptor interaction, the chemokine signaling pathway, the NOD-like receptor signaling pathway, the measles pathway, and the IL-17 signaling pathway. This response is correlative to clinical response in lungs of patients with COVID-19. These results demonstrate that expression of hACE2 via adenovirus delivery system sensitized the mouse to SARS-CoV-2 infection and resulted in the development of a mild COVID-19 phenotype, highlighting the immune and inflammatory host responses to SARS-CoV-2 infection. This rapidly deployable COVID-19 mouse model is useful for preclinical and pathogenesis studies of COVID-19.

引用

页码：79 / 88

页数：10

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