Ebola virus exploits host lncRNA LINC01740 to enhance ATF3 and suppress antiviral immune responses 2259953

Abstract

Abstract Introduction Ebola virus (EBOV) causes a highly lethal hemorrhagic fever marked by uncontrolled cytokine release and impaired antiviral defense. EBOV primarily infects human macrophages, where uncontrolled replication reprograms host transcription and fuels hyperinflammation. Long non-coding RNAs (lncRNAs), potent regulators of transcription and immunity, remain largely unexplored in EBOV pathogenesis. We identified EBOV-induced lncRNAs co-regulated with transcription factors (TFs) in primary human macrophages, revealing a novel mechanism by which EBOV rewires host gene expression to promote immune suppression and persistence Methods Using the highly virulent EBOV (Mayinga variant), we infected primary human macrophages from nine donors. We compared protein-coding and lncRNA transcriptomes of EBOV-infected vs. MOCK-infected macrophages at 24- and 48-hours post-infection. Differentially expressed lncRNAs were correlated with adjacent protein-coding genes to infer cis-regulatory relationships. Functional validation used antisense oligonucleotides, CRISPR interference (CRISPRi), and inducible CRISPR—Cas13d knockdown, followed by qPCR, RNA-seq, and Western blotting Results EBOV infection triggered extensive remodeling of macrophage transcriptome. LINC01740 was strongly induced and tightly co-expressed with its neighboring gene, ATF3, a stress-responsive transcription factor known to repress antiviral signaling. LINC01740 knockdown reduced ATF3 expression in macrophages. ATF3 inhibition restored interferon-beta production, enhanced innate immune activation, and induced strong antiviral responses in EBOV-infected macrophages. Our data show that ATF3 impairs IFN-I responses in macrophages, contributing to immune paralysis Conclusion Our data revealed LINC01740 as a novel host lncRNA co-opted by EBOV to enhance ATF3 and suppress antiviral responses. Here we show a novel LINC01740—ATF3—IFN-I regulatory axis driving immune evasion and viral persistence, highlighting lncRNAs as potential antiviral therapeutic targets Funding Source n/a Topic Categories Viral Immunology (VIR)