SARS-CoV-2 Omicron Variants Show Attenuated Neurovirulence Compared with the Wild-Type Strain in Elderly Human Brain Spheroids
Weikang Chen,
Xiaobing Jiang,
Wei Liang,
Haojie Bai,
Mingze Xu,
Zhe Liu,
Lina Yi,
Yanming Liu,
Yanxia Huang,
Yongxin Zhang,
Lixia Xu,
Baoshu Xie,
Nu Zhang,
Jun Yu,
Jing Lu,
Haipeng Xiao,
Xiaoxing Li
Affiliations
Weikang Chen
Department of Neurosurgery,
The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510000, China.
Xiaobing Jiang
Department of Neurosurgery/Neuro-Oncology, State Key Laboratory of Oncology in South China,
Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center (SYSUCC), Guangzhou 510000, China.
Wei Liang
Institute of Precision Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510000, China.
Haojie Bai
Institute of Precision Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510000, China.
Mingze Xu
Institute of Precision Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510000, China.
Zhe Liu
Guangdong Provincial Institution of Public Health, Guangdong Provincial Center for Disease Control and Prevention, Guangzhou 510000, China.
Lina Yi
Guangdong Provincial Institution of Public Health, Guangdong Provincial Center for Disease Control and Prevention, Guangzhou 510000, China.
Yanming Liu
Institute of Precision Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510000, China.
Yanxia Huang
Department of Neurosurgery,
The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510000, China.
Yongxin Zhang
Institute of Precision Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510000, China.
Lixia Xu
Department of Oncology,
The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510000, China.
Baoshu Xie
Department of Neurosurgery,
The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510000, China.
Nu Zhang
Department of Neurosurgery,
The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510000, China.
Jun Yu
Institute of Precision Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510000, China.
Jing Lu
Guangdong Provincial Institution of Public Health, Guangdong Provincial Center for Disease Control and Prevention, Guangzhou 510000, China.
Haipeng Xiao
Department of Endocrinology,
The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510000, China.
Xiaoxing Li
Institute of Precision Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510000, China.
Infection with severe acute respiratory syndrome coronavirus 2 Omicron variants still causes neurological complications in elderly individuals. However, whether and how aging brains are affected by Omicron variants in terms of neuroinvasiveness and neurovirulence are unknown. Here, we utilize resected paracarcinoma brain tissue from elderly individuals to generate primary brain spheroids (BSs) for investigating the replication capability of live wild-type (WT) strain and Omicron (BA.1/BA.2), as well as the mechanisms underlying their neurobiological effects. We find that both WT and Omicron BA.1/BA.2 are able to enter BSs but weakly replicate. There is no difference between Omicron BA.1/BA.2 and WT strains in neurotropism in aging BSs. However, Omicron BA.1/BA.2 exhibits ameliorating neurological damage. Transcriptional profiling indicates that Omicron BA.1/BA.2 induces a lower neuroinflammatory response than WT strain in elderly BSs, suggesting a mechanistic explanation for their attenuated neuropathogenicity. Moreover, we find that both Omicron BA.1/BA.2 and WT strain infections disrupt neural network activity associated with neurodegenerative disorders by causing neuron degeneration and amyloid-β deposition in elderly BSs. These results uncover Omicron-specific mechanisms and cellular immune responses associated with severe acute respiratory syndrome coronavirus 2-induced neurological complications.
