Abstract

ABSTRACT Rabies virus (RABV) causes severe central nervous system damage, though the underlying mechanisms remain unclear. Circular RNAs (circRNAs) have been identified in various cells and tissues and are known to regulate gene expression in eukaryotes. Here, we investigated the expression patterns of circRNAs in brain tissues from mice infected with two strains of RABV (CVS-11 and SRV9) and compared them to brain tissues from uninfected mice. Differential expression analysis identified 1,306 circRNAs, primarily derived from coding exons, with functional enrichment implicating synaptic and nervous system pathways. Critically, we identified and validated a novel regulatory axis, mmu_circ_0012122/mmu-miR-1843-5p/Sertad2, where mmu_circ_0012122 acts as a sponge for mmu-miR-1843-5p, leading to Sertad2 upregulation. This axis differentially modulated murine nerve cell fate: mmu_circ_0012122 knockdown reduced necrotic and non-viable apoptotic cells, while mmu-miR-1843-5p overexpression suppressed viable apoptosis and necrosis. Comprehensive characterization further identified Sertad2 as a key mediator promoting both nerve cell apoptosis and neuroinflammatory responses during infection. These findings underscored circRNAs as critical regulators of neuronal survival during RABV infection and highlighted the mmu_circ_0012122-driven network as a potential therapeutic target.