Liang jing qi8/11/2023 ![]() ![]() Meanwhile, the cross-protection of host immunity induced by SARS-CoV-2 infection or vaccination against potential pCoV infection was investigated. Herein, we comprehensively characterize the infectivity and pathogenicity of a representative pCoV in comparison with SARS-CoV-2 in cells, organoids, and animal models. However, human infections with pCoVs have not yet been documented, and the potential risk of spillover of pCoVs to humans remains incompletely investigated. Importantly, bioinformatic analysis suggested that the entire receptor binding domain (RBD) of SARS-CoV-2 was introduced through recombination with pCoVs, representing a critical step in the evolution of SARS-CoV-2 to acquire the capability to infect humans 16, 17. Compared with bCoVs, some pCoVs showed high binding affinity to ACE2, the receptor of SARS-CoV-2 14, and functional assays with pseudovirus confirmed that pCoVs are capable of entering a panel of human cells 2, 15. During the search for the natural host of SARS-CoV-2, we and another group independently identified SARS-CoV-2-related pangolin coronaviruses (pCoVs) in trafficked Malayan pangolins 12, 13. A number of viral agents have been identified in pangolins 10, 11, and the global illicit trade of pangolins increases the risks of spillover of pangolin viruses to humans. Pangolins are the only scaled mammal and the most trafficked mammal that is mainly distributed in Asia and Africa 8, 9. The discovery and identification of SARS-CoV-2-related coronaviruses in pangolins were somewhat unexpected. Structural and biochemical analyses also supported the weak ACE2 binding affinity of the bCoV RBD and limited infectivity to human cells 7. Although the newly identified BANAL bCoVs were shown to infect and replicate in some human cells, most bCoVs were not isolated or showed limited replication in human cells 5, 6. Among these bCoVs, RaTG13 detected from the samples of Yunnan Rhinolophus was considered to have the closest relationship with SARS-CoV-2 until several BANAL bCoVs were found in Laos at the beginning of 2022 4, 5. Numerous SARS-like bat coronaviruses (bCoV) have been identified with high genetic similarity (genomic identity > 90%) with SARS-CoV-2. Human coronaviruses mostly originate from animal hosts, and bats are considered to be the natural reservoir hosts of many coronaviruses 1, 2, 3. The origin and evolution of SARS-CoV-2 remain some of the most controversial and mysterious issues in the scientific community and the public. The ongoing coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its variants continues to thrive worldwide, posing unprecedented challenges to public health and socioeconomic development. ![]() Our results provide direct evidence supporting pCoV-GD01 as a potential human pathogen and highlight the potential spillover risk. Interestingly, in vitro neutralization assays and animal heterologous challenge experiments demonstrated that preexisting immunity induced by SARS-CoV-2 infection or vaccination was sufficient to provide at least partial cross-protection against pCoV-GD01 challenge. Remarkably, intranasal inoculation of pCoV-GD01 caused severe lung pathological damage in hACE2 mice and could transmit among cocaged hamsters. pCoV-GD01 showed similar infectivity to SARS-CoV-2 in human cells and organoids. Herein, we comprehensively characterized the infectivity and pathogenicity of a recent pCoV isolate (pCoV-GD01) in human cells and human tracheal epithelium organoids and established animal models in comparison with SARS-CoV-2. A panel of SARS-CoV-2-related coronaviruses have been identified in pangolins, while the infectivity and pathogenicity of these pangolin-origin coronaviruses (pCoV) in humans remain largely unknown. Virus spillover remains a major challenge to public health. ![]()
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