SARS-CoV-2 Reverse Genetics Reveals a Variable Infection Gradient in the Respiratory Tract

被引：1045

作者：

Hou, Yixuan J. ^{[1
]}

Okuda, Kenichi ^{[3
]}

Edwards, Caitlin E. ^{[1
]}

Martinez, David R. ^{[1
]}

Asakura, Takanori ^{[3
]}

Dinnon, Kenneth H., III ^{[2
]}

Kato, Takafumi ^{[3
]}

Lee, Rhianna E. ^{[3
]}

Yount, Boyd L. ^{[1
]}

Mascenik, Teresa M. ^{[3
]}

Chen, Gang ^{[3
]}

Olivier, Kenneth N. ^{[16
]}

Ghio, Andrew ^{[17
]}

Tse, Longping, V ^{[1
]}

Leist, Sarah R. ^{[1
]}

Gralinski, Lisa E. ^{[1
]}

Schafer, Alexandra ^{[1
]}

Dang, Hong ^{[3
]}

Gilmore, Rodney ^{[3
]}

Nakano, Satoko ^{[3
]}

Sun, Ling ^{[3
]}

Fulcher, M. Leslie ^{[3
]}

Livraghi-Butrico, Alessandra ^{[3
]}

Nicely, Nathan, I ^{[4
]}

Cameron, Mark ^{[11
]}

Cameron, Cheryl ^{[12
]}

Kelvin, David J. ^{[10
,18
]}

de Silva, Aravinda ^{[2
]}

Margolis, David M. ^{[2
,5
,6
]}

Markmann, Alena ^{[5
]}

Bartelt, Luther ^{[5
]}

Zumwalt, Ross ^{[13
]}

Martinez, Fernando J. ^{[14
]}

Salvatore, Steven P. ^{[15
]}

Borczuk, Alain ^{[15
]}

Tata, Purushothama R. ^{[9
]}

Sontake, Vishwaraj ^{[9
]}

Kimple, Adam ^{[7
]}

Jaspers, Ilona ^{[8
]}

O'Neal, Wanda K. ^{[3
]}

Randell, Scott H. ^{[3
]}

Boucher, Richard C. ^{[3
]}

Baric, Ralph S. ^{[1
,2
]}

机构：

[1] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC 27515 USA

[2] Univ N Carolina, Dept Microbiol & Immunol, Chapel Hill, NC 27515 USA

[3] Univ N Carolina, Marsico Lung Inst, Chapel Hill, NC 27515 USA

[4] Univ N Carolina, Prot Express & Purificat Core, Chapel Hill, NC 27515 USA

[5] Univ N Carolina, Dept Med, Chapel Hill, NC 27515 USA

[6] Univ N Carolina, HIV Cure Ctr, Chapel Hill, NC 27515 USA

[7] Univ N Carolina, Dept Otolaryngol, Chapel Hill, NC 27515 USA

[8] Univ N Carolina, Dept Pediat, Chapel Hill, NC 27515 USA

[9] Duke Univ, Med Ctr, Dept Cell Biol, Regenerat Next Initiat, Durham, NC 27710 USA

[10] Dalhousie Univ, Canadian Ctr Vaccinol, Dept Microbiol & Immunol, Halifax, NS, Canada

[11] Case Western Reserve Univ, Dept Populat & Quantitat Hlth Sci, Cleveland, OH 44106 USA

[12] Case Western Reserve Univ, Dept Nutr, Cleveland, OH 44106 USA

[13] Univ New Mexico, Dept Pathol, Albuquerque, NM 87131 USA

[14] Cornell Univ, Joan & Sanford I Weill Med Coll, Div Pulm & Crit Care Med, New York, NY 10021 USA

[15] Cornell Univ, Joan & Sanford I Weill Med Coll, Dept Pathol, New York, NY 10021 USA

[16] NHLBI, Lab Chron Airway Infect, Pulm Branch, NIH, Bldg 10, Bethesda, MD 20892 USA

[17] US EPA, Natl Hlth & Environm Effects Res Lab, Chapel Hill, NC USA

[18] Shantou Univ, Lab Immunol, Med Coll, Shantou, Guangdong, Peoples R China

来源：

CELL | 2020年 / 182卷 / 02期

关键词：

CORONAVIRUS SPIKE PROTEIN; ENZYME; 2; ACE2; SARS CORONAVIRUS; CELL ENTRY; CDNA-CLONE; MERS-COV; VIRUS; NEUTRALIZATION; ACTIVATION; ASPIRATION;

D O I：

10.1016/j.cell.2020.05.042

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：

The mode of acquisition and causes for the variable clinical spectrum of coronavirus disease 2019 (COVID-19) remain unknown. We utilized a reverse genetics system to generate a GFP reporter virus to explore severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pathogenesis and a luciferase reporter virus to demonstrate sera collected from SARS and COVID-19 patients exhibited limited cross-CoV neutralization. High-sensitivity RNA in situ mapping revealed the highest angiotensin-converting enzyme 2 (ACE2) expression in the nose with decreasing expression throughout the lower respiratory tract, paralleled by a striking gradient of SARS-CoV-2 infection in proximal (high) versus distal (low) pulmonary epithelial cultures. COVID-19 autopsied lung studies identified focal disease and, congruent with culture data, SARS-CoV-2-infected ciliated and type 2 pneumocyte cells in airway and alveolar regions, respectively. These findings highlight the nasal susceptibility to SARS-CoV-2 with likely subsequent aspiration-mediated virus seeding to the lung in SARS-CoV-2 pathogenesis. These reagents provide a foundation for investigations into virus-host interactions in protective immunity, host susceptibility, and virus pathogenesis.

引用

页码：429 / +

页数：32

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