Neuroinflammatory and transcriptional dynamics during SARS-CoV-2 infection in KRT18-hACE2 mouse brain

TL;DR

This study examines how SARS-CoV-2 affects the brain over time in mice, revealing dynamic changes in inflammation and gene activity linked to neurological damage.

Contribution

The study provides a time-resolved molecular analysis of SARS-CoV-2-induced neuroinflammation and metabolic stress in the brain.

Findings

SARS-CoV-2 causes neuroinflammation and neuronal apoptosis in cortical neurons of infected mice.

Transcriptome analysis shows early changes in synaptic processes and later immune activation and mitochondrial dysfunction.

Reduced CX3CL1 and elevated inflammatory cytokines suggest impaired neuron-microglia communication and energy exhaustion.

Abstract

Neurological complications are increasingly recognized as a significant consequence of COVID-19; however, time-resolved, brain-specific characterization of transcriptional alterations underlying SARS-CoV-2–associated neuroinflammation and neuronal injury remain limited. We hypothesized that brain transcriptional responses evolve dynamically during acute SARS-CoV-2 infection, resulting in temporal transcriptional programs.

KRT18-hACE2 transgenic mice were intranasally inoculated with SARS-CoV-2. Brain was harvested at 4 and 6 days post-infection (dpi) for analyses.

Immunohistochemical analyses confirmed a broad spectrum of viral neurotropism and gliotropism, accompanied by an increased apoptotic burden, particularly in cortical neurons (ClCas3/SATB2+). Robust activation of myeloid cells (Iba1+/CD68+) provided evidence of neuroinflammation. Cytokine/chemokine profiling demonstrated pronounced upregulation of inflammatory mediators (CXCL10, IL-12p40, CCL12), alongside reduced CX3CL1, suggesting impaired neuron–microglia communication. Whole-transcriptome and gene ontology analyses uncovered stage-dependent molecular programs, with early alterations at 4 dpi enriched in protein ubiquitination, vesicle trafficking, and synaptic processes, followed by intensified innate immune activation and engagement of chromosomal maintenance pathways at 6 dpi. In parallel, pronounced suppression of mitochondrial function at 6 dpi, pointing to energy exhaustion and transcriptional-translational discordance, as supported by digital PCR and a substantial reduction in COXIV protein levels.

These findings provide a time-resolved molecular landscape of SARS-CoV-2–induced neuroinflammation and metabolic stress, highlighting CNS vulnerability during severe infection and suggesting pathways potentially relevant to COVID-19-associated sequelae.

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