Pathogenicity and Transcriptomic Profiling Revealed Activation of Apoptosis and Pyroptosis in Brain of Mice Infected with the Beta Variant of SARS-CoV-2.

Han LI; Bao Ying HUANG; Gao Qian ZHANG; Fei YE; Li ZHAO; Wei Bang HUO; Zhong Xian ZHANG; Wen WANG; Wen Ling WANG; Xiao Ling SHEN; Chang Cheng WU; Wen Jie TAN

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Pathogenicity and Transcriptomic Profiling Revealed Activation of Apoptosis and Pyroptosis in Brain of Mice Infected with the Beta Variant of SARS-CoV-2.

Author: Han LI ¹ ; Bao Ying HUANG ² ; Gao Qian ZHANG ³ ; Fei YE ² ; Li ZHAO ² ; Wei Bang HUO ² ; Zhong Xian ZHANG ¹ ; Wen WANG ² ; Wen Ling WANG ² ; Xiao Ling SHEN ³ ; Chang Cheng WU ² ; Wen Jie TAN ¹
Author Information

1. National Key Laboratory of Intelligent Tracking and Forecasting for Infectious Diseases (NITFID), NHC Key Laboratory of Biosafety, National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing 100052, China;School of Public Health, Baotou Medical College, Baotou 014040, Inner Mongolia, China.
2. National Key Laboratory of Intelligent Tracking and Forecasting for Infectious Diseases (NITFID), NHC Key Laboratory of Biosafety, National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing 100052, China.
3. Department of Microbiology, Basic Medical College, Inner Mongolia Medical University, Hohhot 010010, Inner Mongolia, China.
Publication Type:Journal Article
Keywords: Beta variant of SARS-CoV-2; Cell death; Encephalitis; Neuronal injury; Transcriptomics
MeSH: Animals; COVID-19/genetics*; Mice; Brain/metabolism*; Apoptosis; Mice, Inbred C57BL; SARS-CoV-2/physiology*; Pyroptosis; Gene Expression Profiling; Transcriptome; Male; Female
From: Biomedical and Environmental Sciences 2025;38(9):1082-1094
CountryChina
Language:English
Abstract: OBJECTIVE:Patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection frequently develop central nervous system damage, yet the mechanisms driving this pathology remain unclear. This study investigated the primary pathways and key factors underlying brain tissue damage induced by the SARS-CoV-2 beta variant (lineage B.1.351).
METHODS:K18-hACE2 and C57BL/6 mice were intranasally infected with the SARS-CoV-2 beta variant. Viral replication, pathological phenotypes, and brain transcriptomes were analyzed. Gene Ontology (GO) analysis was performed to identify altered pathways. Expression changes of host genes were verified using reverse transcription-quantitative polymerase chain reaction and Western blot.
RESULTS:Pathological alterations were observed in the lungs of both mouse strains. However, only K18-hACE2 mice exhibited elevated viral RNA loads and infectious titers in the brain at 3 days post-infection, accompanied by neuropathological injury and weight loss. GO analysis of infected K18-hACE2 brain tissue revealed significant dysregulation of genes associated with innate immunity and antiviral defense responses, including type I interferons, pro-inflammatory cytokines, Toll-like receptor signaling components, and interferon-stimulated genes. Neuroinflammation was evident, alongside activation of apoptotic and pyroptotic pathways. Furthermore, altered neural cell marker expression suggested viral-induced neuroglial activation, resulting in caspase 4 and lipocalin 2 release and disruption of neuronal molecular networks.
CONCLUSION:These findings elucidate mechanisms of neuropathogenicity associated with the SARS-CoV-2 beta variant and highlight therapeutic targets to mitigate COVID-19-related neurological dysfunction.