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

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SARS-CoV-2 Reverse Genetics Reveals a Variable Infection Gradient in the Respiratory Tract.
Cell ( IF 64.5 ) Pub Date : 2020-05-27 , DOI: 10.1016/j.cell.2020.05.042
Yixuan J Hou ₁ , Kenichi Okuda ₂ , Caitlin E Edwards ₁ , David R Martinez ₁ , Takanori Asakura ₂ , Kenneth H Dinnon ₃ , Takafumi Kato ₂ , Rhianna E Lee ₂ , Boyd L Yount ₁ , Teresa M Mascenik ₂ , Gang Chen ₂ , Kenneth N Olivier ₄ , Andrew Ghio ₅ , Longping V Tse ₁ , Sarah R Leist ₁ , Lisa E Gralinski ₁ , Alexandra Schäfer ₁ , Hong Dang ₂ , Rodney Gilmore ₂ , Satoko Nakano ₂ , Ling Sun ₂ , M Leslie Fulcher ₂ , Alessandra Livraghi-Butrico ₂ , Nathan I Nicely ₆ , Mark Cameron ₇ , Cheryl Cameron ₈ , David J Kelvin ₉ , Aravinda de Silva ₃ , David M Margolis ₁₀ , Alena Markmann ₁₁ , Luther Bartelt ₁₁ , Ross Zumwalt ₁₂ , Fernando J Martinez ₁₃ , Steven P Salvatore ₁₄ , Alain Borczuk ₁₄ , Purushothama R Tata ₁₅ , Vishwaraj Sontake ₁₅ , Adam Kimple ₁₆ , Ilona Jaspers ₁₇ , Wanda K O'Neal ₂ , Scott H Randell ₂ , Richard C Boucher ₂ , Ralph S Baric ₁₈

Affiliation

Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Marsico Lung Institute, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Laboratory of Chronic Airway Infection, Pulmonary Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
National Health and Environmental Effects Research Laboratory, Environmental Protection Agency, Chapel Hill, NC, USA.
Protein Expression and Purification Core, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Department of Population and Quantitative Health Science, Case Western Reserve University, Cleveland, OH, USA.
Department of Nutrition, Case Western Reserve University, Cleveland, OH, USA.
Department of Microbiology and Immunology, Canadian Center for Vaccinology, Dalhousie University, Halifax, NS, Canada; Laboratory of Immunology, Shantou University Medical College, Shantou, Guangdong, China.
Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; HIV Cure Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Department of Pathology, University of New Mexico, Albuquerque, NM, USA.
Division of Pulmonary and Critical Care Medicine, Joan & Sanford I. Weill Medical College of Cornell University, New York, NY, USA.
Department of Pathology, Joan & Sanford I. Weill Medical College of Cornell University, New York, NY, USA.
Department of Cell Biology, Regeneration Next Initiative, Duke University Medical Center, Durham, NC, USA.
Department of Otolaryngology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Department of Pediatrics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.

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.

中文翻译：

SARS-CoV-2 反向遗传学揭示了呼吸道中可变的感染梯度。

2019 年冠状病毒病 (COVID-19) 的感染方式和不同临床谱的原因仍不清楚。我们利用反向遗传学系统生成了 GFP 报告病毒，以探索严重急性呼吸综合征冠状病毒 2 (SARS-CoV-2) 的发病机制，并利用荧光素酶报告病毒来证明从 SARS 和 COVID-19 患者收集的血清表现出有限的交叉 CoV 中和作用。高灵敏度 RNA原位图谱显示，血管紧张素转换酶 2 (ACE2) 在鼻子中的表达量最高，而在整个下呼吸道的表达量逐渐减少，同时近端（高）与远端的 SARS-CoV-2 感染也存在显着梯度（低）肺上皮培养物。COVID-19 尸检肺部研究确定了局灶性疾病，并且与培养数据一致，分别发现了气道和肺泡区域中感染 SARS-CoV-2 的纤毛细胞和 2 型肺细胞。这些发现强调了鼻腔对 SARS-CoV-2 的易感性，以及随后在 SARS-CoV-2 发病机制中可能通过吸入介导的病毒播散到肺部。这些试剂为研究病毒与宿主在保护性免疫、宿主易感性和病毒发病机制方面的相互作用奠定了基础。

更新日期：2020-07-23

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