Ebola virus (EBOV) infection causes severe hemorrhagic fever marked by dysregulated cytokine production, impaired antiviral defenses, and multi-organ failure. Macrophages are primary targets of EBOV, and viral replication profoundly alters macrophage transcriptional programs, driving hyperinflammation. Although long non-coding RNAs (lncRNAs) are increasingly recognized as regulators of immunity and viral pathogenesis, their roles in EBOV infection remain poorly understood. We performed comprehensive transcriptomic profiling of primary human monocyte-derived macrophages infected with the highly pathogenic EBOV Mayinga variant. Infection triggered extensive remodeling of both coding and non-coding transcriptomes, including hundreds of differentially expressed lncRNAs. Functional analysis of neighboring protein-coding genes of EBOV-induced lncRNAs (EVILs) revealed enrichment of pathways linked to cytokine signaling, transcriptional regulation, and cell signaling, all of which are central to Ebola virus disease (EVD) pathogenesis. Among the most strongly induced EVILs, LINC01740 and its neighboring protein-coding gene, Activating Transcription Factor 3 (ATF3), were significantly upregulated. Antisense oligonucleotide-mediated inhibition of LINC01740 reduced ATF3 mRNA and protein levels. CRISPR/Cas13d-mediated knockdown of ATF3 restored type I interferon (IFN-I) signaling and antiviral gene expression in EBOV-infected macrophages. Mechanistically, ATF3 functions as a negative regulator of IFN-I and type I interferon-stimulated gene expression, thereby suppressing antiviral immune responses in EBOV-infected macrophages. Together, these findings identify a previously unrecognized LINC01740-ATF3-IFN-I regulatory axis that EBOV exploits to promote immune suppression and viral replication.
O. Shtanko, Tanuj Gunturu, Anumarla Gopal et al.· bioRxiv· 0 citations
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
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
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
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
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Viral Immunology (VIR)
Narasimha Tanuj Gunturu, Anumarla Gopal, Marija Djurkovic-Lopez et al.· Journal of Immunology· 0 citations
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