SARS-CoV-2感染北平顶猴（<i>Macaca leonina</i>）呈现病毒快速清除及持续的免疫反应

Tian-Zhang Song; Hong-Yi Zheng; Jian-Bao Han; Xiao-Li Feng; Feng-Liang Liu; Xiang Yang; Lin Jin; Rong-Hua Luo; Ren-Rong Tian; Chao Liu; Ming-Hua Li; Hou-Rong Cai; Yong-Tang Zheng

doi:10.24272/j.issn.2095-8137.2020.334

SARS-CoV-2感染北平顶猴（Macaca leonina）呈现病毒快速清除及持续的免疫反应

doi: 10.24272/j.issn.2095-8137.2020.334

宋天章^{1, #},
郑宏毅^{1, #},
韩建保^{2, #},
冯小丽²,
刘丰亮¹,
杨翔²,
靳林¹,
罗荣华¹,
田仁荣¹,
刘超³,
李明华²,
蔡后荣⁴,
郑永唐^{1, 2, 3, ,}

1.
中国科学院昆明动物研究所中国科学院动物模型与人类疾病机制重点实验室，KIZ-CUHK常见疾病生物资源与分子研究联合实验室，云南昆明650223，中国
2.
中国科学院昆明动物研究所国家昆明高等级生物安全灵长类动物实验中心，中国科学院生物安全大科学研究中心，云南昆明650107，中国
3.
中国科学院昆明动物研究所国家非人灵长类实验动物资源库，模式动物表型与遗传研究国家重大科技基础设施（灵长类设施），云南昆明 650107，中国
4.
南京大学附属鼓楼医院呼吸与危重症医学科，江苏南京 210008，中国

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出版历程
- 收稿日期: 2020-11-17
- 录用日期: 2021-04-28
- 网络出版日期: 2021-05-13
- 刊出日期: 2021-05-18

Northern pig-tailed macaques (Macaca leonina) infected with SARS-CoV-2 show rapid viral clearance and persistent immune response

1.
Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences/Key Laboratory of Bioactive Peptides of Yunnan Province, KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan 650223, China
2.
Kunming National High-Level Biosafety Research Center for Non-Human Primates, Center for Biosafety Mega-Science, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan 650107, China
3.
National Resource Center for Non-Human Primates, and National Research Facility for Phenotypic & Genetic Analysis of Model Animals (Primate Facility), Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan 650107, China
4.
Department of Respiratory and Critical Care Medicine, Affiliated Drum Tower Hospital of Nanjing University, Nanjing, Jiangsu 210008, China

Funds: This work was partly supported by the National Key R&D Program of China (2020YFC0842000), National Science and Technology Major Projects of Infectious Disease Funds (2017ZX10304402, 2018ZX10301406-003), the National Natural Science Foundation of China (U1802284, U1902210), National Resource Center for Non-Human Primates

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Corresponding author: E-mail: zhengyt@mail.kiz.ac.cn

#These authors contributed equally to this work

摘要

摘要: SARS-CoV-2感染引起的新型冠状病毒肺炎疫情已成为21世纪全球最重要的公共卫生突发事件。目前，SARS-CoV-2感染非人灵长类动物模型被认为是进行新型冠状病毒肺炎病理损伤特征及致病机制研究的金标准。该研究中，我们成功构建SARS-CoV-2感染北平顶猴（Macaca leonina）实验动物模型，发现北平顶猴可有效支持病毒复制。与恒河猴实验动物模型相比，SARS-CoV-2感染北平顶猴肺组织、鼻拭子、咽拭子及肛拭子中病毒快速清除，这可能与北平顶猴感染后肺组织中干扰素的高表达有关。但是，与恒河猴相比，感染后第二周北平顶猴呈现持续甚至更为严重的炎症反应及临床症状。上述结果表明，病毒清除可能与新型冠状病毒肺炎的疾病进展无关，SARS-CoV-2感染北平顶猴可被视为重症模型用于新型冠状病毒肺炎相关研究。
- SARS-CoV-2 /
- 新型冠状病毒肺炎 /
- 灵长类动物模型 /
- 北平顶猴 /
- 免疫应答
Abstract: Coronavirus disease 2019 (COVID-19), which is caused by severe acute respiratory syndrome coronavirus (SARS-CoV-2), has become an unprecedented global health emergency. At present, SARS-CoV-2-infected nonhuman primates are considered the gold standard animal model for COVID-19 research. Here, we showed that northern pig-tailed macaques (Macaca leonina, NPMs) supported SARS-CoV-2 replication. Furthermore, compared with rhesus macaques, NPMs showed rapid viral clearance in lung tissues, nose swabs, throat swabs, and rectal swabs, which may be due to higher expression of interferon (IFN)-α in lung tissue. However, the rapid viral clearance was not associated with good outcome. In the second week post infection, NPMs developed persistent or even more severe inflammation and body injury compared with rhesus macaques. These results suggest that viral clearance may have no relationship with COVID-19 progression and SARS-CoV-2-infected NPMs could be considered as a critically ill animal model in COVID-19 research.
- SARS-CoV-2 /
- COVID-19 /
- Primate animal models /
- Northern pig-tailed macaques (Macaca leonina) /
- Immune response
#These authors contributed equally to this work
注释:

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1. Clearance of SARS-CoV-2 in NPMs

A: Comparison of viral loads (VL) in nose, rectal, and throat swabs between NPMs and RMs. B: Comparison of viral loads in lung tissues between NPMs and RMs. C: Comparison of IFN-α+, IL-1β+, and IL-6+ cells in lung tissues between NPMs and RMs. Positive ratio=(counts of macaques with SARS-CoV-2 + swabs or lung points/counts of macaques)×100%. ^*: 0.01<P<0.05; ^**: 0.001<P≤0.01. ns: No significance. RMs: Rhesus macaques (Macaca mulatta); NPMs: Northern pig-tailed macaques (Macaca leonina).

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Figure 2. Body injuries and immune response in NPMs

A: Body temperature in NPMs euthanized at 15 dpi. B: Concentrations of BUN and ALT in serum during SARS-CoV-2 infection (black icon: NPMs euthanized at 7 dpi; gray icon: NPMs euthanized at 15 dpi). C: Number of immune cells in peripheral blood (black icon: NPMs euthanized at 7 dpi; gray icon: NPMs euthanized at 15 dpi). D: Concentrations of cytokines in lung tissue. E: Immunofluorescence staining of immune cells in lungs. ^*: 0.01<P<0.05; ns: No significance. RMs: Rhesus macaques (Macaca mulatta); NPMs: Northern pig-tailed macaques (Macaca leonina); WBC: White blood cell.

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SARS-CoV-2感染北平顶猴（Macaca leonina）呈现病毒快速清除及持续的免疫反应

doi: 10.24272/j.issn.2095-8137.2020.334

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Northern pig-tailed macaques (Macaca leonina) infected with SARS-CoV-2 show rapid viral clearance and persistent immune response

Corresponding author: E-mail: zhengyt@mail.kiz.ac.cn

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SARS-CoV-2感染北平顶猴（Macaca leonina）呈现病毒快速清除及持续的免疫反应

doi: 10.24272/j.issn.2095-8137.2020.334

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Northern pig-tailed macaques (Macaca leonina) infected with SARS-CoV-2 show rapid viral clearance and persistent immune response

Corresponding author: E-mail: zhengyt@mail.kiz.ac.cn

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