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Epstein-Barr Virus miR-BART6-3p Inhibits the RIG-I Pathway
Yuanjun Lu1, Zailong Qin, Jia Wang
1Key Laboratory of Carcinogenesis of the Chinese Ministry of Health, Xiangya Hospital, Changsha, China.
Abstract:
Recognition of viral pathogen-associated molecular patterns by pattern recognition receptors (PRRs) is the first step in the initiation of a host innate immune response. As a PRR, RIG-I detects either viral RNA or replication transcripts. Avoiding RIG-I recognition is a strategy employed by viruses for immune evasion. Epstein-Barr virus (EBV) infects the majority of the human population worldwide. During the latent infection period there are only a few EBV proteins expressed, whereas EBV-encoded microRNAs, such as BART microRNAs, are highly expressed. BART microRNAs regulate both EBV and the host's gene expression, modulating virus proliferation and the immune response. Here, through gene expression profiling, we found that EBV miR-BART6-3ps inhibited genes of RIG-I-like receptor signaling and the type I interferon (IFN) response. We demonstrated that miR-BART6-3p rather than other BARTs specifically suppressed RIG-I-like receptor signaling-mediated IFN-β production. RNA-seq was used to analyze the global transcriptome change upon EBV infection and miR-BART6-3p mimics transfection, which revealed that EBV infection-triggered immune response signaling can be repressed by miR-BART6-3p overexpression. Furthermore, miR-BART6-3p inhibited the EBV-triggered IFN-β response and facilitated EBV infection through targeting the 3'UTR of RIG-I mRNA. These findings provide new insights into the mechanism underlying the strategies employed by EBV to evade immune surveillance.
Insights
Epstein-Barr virus microRNA miR-BART6-3p suppresses the RIG-I-like receptor signaling pathway and type I interferon response. This viral immune evasion strategy targets RIG-I mRNA, facilitating Epstein-Barr virus infection.
Area of Science:
- Immunology
- Virology
- Molecular Biology
Background:
- Innate immunity relies on pattern recognition receptors (PRRs) like RIG-I to detect viral RNA and initiate host defense.
- Viruses often evade immune detection by inhibiting PRR signaling.
- Epstein-Barr virus (EBV) is a widespread human herpesvirus with a complex interplay of protein and microRNA expression during infection.
Purpose of the Study:
- To investigate the role of EBV-encoded BART microRNAs in modulating host innate immune responses.
- To determine if specific BART microRNAs interfere with RIG-I-like receptor signaling and type I interferon production.
- To elucidate the molecular mechanisms by which EBV evades immune surveillance.
Main Methods:
- Gene expression profiling to identify cellular pathways affected by EBV infection and BART microRNAs.
- RNA-sequencing (RNA-seq) to analyze global transcriptome changes.
- Experimental validation of miR-BART6-3p's specific inhibitory effect on RIG-I-like receptor signaling and IFN-β production.
- Luciferase assays to confirm targeting of RIG-I mRNA by miR-BART6-3p.
Main Results:
- EBV miR-BART6-3p was found to significantly inhibit genes involved in RIG-I-like receptor signaling and the type I interferon (IFN) response.
- miR-BART6-3p specifically suppressed IFN-β production mediated by RIG-I-like receptor signaling, distinguishing it from other BART microRNAs.
- RNA-seq analysis revealed that miR-BART6-3p overexpression repressed EBV infection-triggered immune signaling pathways.
- miR-BART6-3p directly targets the 3' untranslated region (3'UTR) of RIG-I mRNA, inhibiting its expression and facilitating EBV infection.
Conclusions:
- EBV utilizes miR-BART6-3p as a key component of its immune evasion strategy.
- miR-BART6-3p effectively dampens the host's RIG-I-mediated innate immune response, particularly the type I IFN pathway.
- Targeting RIG-I mRNA by miR-BART6-3p is a crucial mechanism for EBV to overcome immune surveillance and promote viral persistence.
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