# 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.

## Key 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.