Transcriptomic landscape of pseudorabies virus-induced encephalitis reveals key lncRNAs involved in host–neurotropic virus interactions

Pseudorabies virus (PRV) infection causes fatal encephalitis across various species, a condition known as pseudorabies encephalitis (PRE). However, the molecular mechanisms underlying PRE remain poorly understood. Long noncoding RNAs (lncRNAs) have emerged as important regulators of gene expression in neurological diseases and viral infections. This study explores genome-wide transcriptional alterations in a mouse model of PRV-induced encephalitis. The intranasal inoculation of mice with PRV induced severe encephalitis, characterized by high viral loads, significant inflammatory responses, and the onset of neurological symptoms. RNA-seq analysis revealed 683 differentially expressed (DE) mRNAs and 179 DElncRNAs in PRV-infected brains compared with controls. Functional and pathway analyses revealed that PRE involves neurodegeneration and diverse immune responses, reflecting the complex interplay between viral evasion strategies and host defenses. Co-expression network analysis, supported by experimental validation, identified several lncRNAs as central hubs interacting with multiple immune-related genes and exhibiting cell type-specific expression pattern. Notably, ZFAS1 was prominently dysregulated in PRV-infected microglia and showed extensive co-expression connectivity. Knockdown of ZFAS1 modulated microglia-driven inflammation without altering viral replication, underscoring its potential as a therapeutic target for mitigating neuroinflammation in virus-associated neurological diseases. The identification of key lncRNAs and their potential regulatory roles deepens our understanding of disease mechanisms, while offering new avenues for therapeutic intervention in neurotropic viral infections.