Postdoctoral Scientist Texas Biomedical Research Institute SAN ANTONIO, Texas, United States
Disclosure(s):
Narasimha Tanuj Gunturu, MVSc, PhD: No financial relationships to disclose
Introduction/Rationale: 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
