Infectivity, pathogenicity, and immune protection of the pangolin-origin SARS-CoV-2 related coronavirus

The natural host of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remains elusive. A panel of SARS-CoV-2-related coronaviruses have been identified in pangolins, while the infectivity and pathogenicity of these pangolin-origin coronaviruses (pCoV) to human remains largely unknown. Herein, we comprehensively characterized the infectivity and pathogenicity of pCoV-GD01, the most closest pCoV to SARS-CoV-2, in human cells, human tracheal epithelium organoids, and established animal models in comparision with. The results show that pCoV-GD01 showed similar infectivity to SARS-CoV-2 in human cells and organoids. Remarkably, intranasal inoculation of pCoV-GD01 caused severe lung pathological damage in hACE2 mice, and could establish efficient transmission among co-caged hamsters. Interestingly, in-depth antigenic analysis and animal heterologous challenge experiments demonstrate that pre-existing immunity induced by SARS-CoV-2 infection or vaccination was sufficient to provide cross-protection against pCoV-GD01 challenge. These collective results highlight the potential risk of persistent spillover from animal hosts like the pangolin, and the COVID-19 pandemic and massive vaccination have reduced the possibility of pCoVs circulation in mankind. Human airway epithelium primary cells were induced to generate 2D airway organoids. Then, SARS-CoV-2 and pCoV-GD01 used to infect the organoids. Samples were harvested for transcriptome sequencing.

严重急性呼吸综合征冠状病毒2（SARS-CoV-2）的自然宿主至今仍未明确。研究团队已在穿山甲体内鉴定出多株与SARS-CoV-2亲缘相关的冠状病毒，但此类穿山甲来源冠状病毒（pCoV）对人体的感染性与致病性仍鲜为人知。为此，本研究以与SARS-CoV-2亲缘关系最近的穿山甲来源冠状病毒pCoV-GD01为对象，在人体细胞、人气管上皮类器官中全面表征其感染性与致病性，并构建动物模型与SARS-CoV-2进行对比分析。研究结果显示，pCoV-GD01在人体细胞及类器官中展现出与SARS-CoV-2相近的感染性。值得注意的是，经鼻接种pCoV-GD01可在人血管紧张素转换酶2（hACE2）小鼠体内引发严重的肺部病理损伤，且能在同笼饲养的仓鼠之间实现高效传播。有趣的是，深入的抗原分析与动物异源攻毒实验证实，由SARS-CoV-2感染或疫苗接种诱导的预存免疫，足以提供针对pCoV-GD01攻毒的交叉保护。综合上述研究结果，本研究凸显了穿山甲这类动物宿主持续发生病毒跨种传播的潜在风险；同时，COVID-19大流行与大规模疫苗接种已降低了pCoV在人群中传播的可能性。本研究诱导人呼吸道上皮原代细胞构建二维呼吸道类器官，随后用SARS-CoV-2与pCoV-GD01感染该类器官，并收集样本进行转录组测序。