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Pathogenicity and Transcriptomic Profiling Revealed Activation of Apoptosis and Pyroptosis in Brain of Mice Infected
Han Li1, Bao Ying Huang2, Gao Qian Zhang3
1National 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.
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.
Insights
The SARS-CoV-2 beta variant causes brain damage by triggering innate immunity and inflammatory pathways in K18-hACE2 mice. This study reveals key mechanisms of neuropathogenicity and potential therapeutic targets for COVID-19 neurological issues.
Area of Science:
- Neuroscience
- Virology
- Immunology
Background:
- Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection often leads to central nervous system damage.
- The precise mechanisms underlying SARS-CoV-2-induced neuropathology are not fully understood.
Purpose of the Study:
- To investigate the pathways and factors involved in brain tissue damage caused by the SARS-CoV-2 beta variant (lineage B.1.351).
Main Methods:
- K18-hACE2 and C57BL/6 mice were infected with the SARS-CoV-2 beta variant.
- Viral replication, pathology, and brain transcriptomes were analyzed.
- Gene Ontology (GO) analysis identified altered pathways; gene expression was validated via RT-qPCR and Western blot.
Main Results:
- K18-hACE2 mice showed elevated viral loads and neuropathological injury in the brain.
- Significant dysregulation of innate immunity and antiviral response genes (interferons, cytokines, TLRs) was observed.
- Neuroinflammation, apoptosis, pyroptosis, and neuroglial activation were evident, disrupting neuronal networks.
Conclusions:
- The SARS-CoV-2 beta variant induces neuropathogenicity through innate immune and inflammatory pathways.
- Findings highlight potential therapeutic targets for mitigating COVID-19-related neurological dysfunction.
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