State Key Laboratory of Emerging Infectious Diseases, Department of Microbiology, and Carol Yu Centre for Infection, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong Special Administrative Region, China.
State Key Laboratory of Emerging Infectious Diseases, Department of Microbiology, and Carol Yu Centre for Infection, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong Special Administrative Region, China; Department of Infectious Disease and Microbiology, The University of Hong Kong-Shenzhen Hospital, Shenzhen, Guangdong Province, China; Centre for Virology, Vaccinology and Therapeutics, Hong Kong Science and Technology Park, Hong Kong Special Administrative Region, China; Academician Workstation of Hainan Province, Hainan Medical University-The University of Hong Kong Joint Laboratory of Tropical Infectious Diseases, Hainan Medical University, Haikou, Hainan, China; and The University of Hong Kong, Pokfulam, Hong Kong Special Administrative Region, China; Department of Microbiology, Queen Mary Hospital, Pokfulam, Hong Kong Special Administrative Region, China; Guangzhou Laboratory, Guangdong Province, China.
EBioMedicine. 2023 Sep;95:104753. doi: 10.1016/j.ebiom.2023.104753. Epub 2023 Aug 12.
Among the Omicron sublineages that have emerged, BA.1, BA.2, BA.5, and their related sublineages have resulted in the largest number of infections. While recent studies demonstrated that all Omicron sublineages robustly escape neutralizing antibody response, it remains unclear on whether these Omicron sublineages share any pattern of evolutionary trajectory on their replication efficiency and intrinsic pathogenicity along the respiratory tract.
We compared the virological features, replication capacity of dominant Omicron sublineages BA.1, BA.2 and BA.5 in the human nasal epithelium, and characterized their pathogenicity in K18-hACE2, A129, young C57BL/6, and aged C57BL/6 mice.
We found that BA.5 replicated most robustly, followed by BA.2 and BA.1, in the differentiated human nasal epithelium. Consistently, BA.5 infection resulted in higher viral gene copies, infectious viral titres and more abundant viral antigen expression in the nasal turbinates of the infected K18-hACE2 transgenic mice. In contrast, the Omicron sublineages are continuously attenuated in lungs of infected K18-hACE2 and C57BL/6 mice, leading to decreased pathogenicity. Nevertheless, lung manifestations remain severe in Omicron sublineages-infected A129 and aged C57BL/6 mice.
Our results suggested that the Omicron sublineages might be gaining intrinsic replication fitness in the upper respiratory tract, therefore highlighting the importance of global surveillance of the emergence of hyper-transmissive Omicron sublineages. On the contrary, replication and intrinsic pathogenicity of Omicron is suggested to be further attenuated in the lower respiratory tract. Effective vaccination and other precautions should be in place to prevent severe infections in the immunocompromised populations at risk.
A full list of funding bodies that contributed to this study can be found in the Acknowledgements section.
在出现的奥密克戎亚谱系中，BA.1、BA.2、BA.5 及其相关亚谱系导致了最多的感染。虽然最近的研究表明，所有奥密克戎亚谱系都能强有力地逃避中和抗体的反应，但这些奥密克戎亚谱系在其复制效率和呼吸道固有致病性方面是否存在任何进化轨迹的模式尚不清楚。
我们比较了主导奥密克戎亚谱系 BA.1、BA.2 和 BA.5 在人鼻腔上皮中的病毒学特征和复制能力，并在 K18-hACE2、A129、年轻 C57BL/6 和老年 C57BL/6 小鼠中对其致病性进行了表征。
我们发现，BA.5 在分化的人鼻腔上皮中复制最活跃，其次是 BA.2 和 BA.1。同样，BA.5 感染导致感染的 K18-hACE2 转基因小鼠鼻鼻甲中的病毒基因拷贝数、感染性病毒滴度和更多的病毒抗原表达更高。相比之下，奥密克戎亚谱系在感染的 K18-hACE2 和 C57BL/6 小鼠的肺部不断减弱，导致致病性降低。然而，奥密克戎亚谱系感染的 A129 和老年 C57BL/6 小鼠的肺部表现仍然严重。
我们的结果表明，奥密克戎亚谱系可能在上呼吸道获得内在复制适应性，因此强调了对高传染性奥密克戎亚谱系出现进行全球监测的重要性。相反，奥密克戎的复制和内在致病性在呼吸道下部被认为进一步减弱。应该采取有效的疫苗接种和其他预防措施，以防止免疫功能低下的高危人群发生严重感染。
本研究的资助机构的完整清单可在致谢部分找到。
