An Epstein-Barr Virus MicroRNA Blocks Interleukin-1 (IL-1) Signaling by Targeting IL-1 Receptor 1

Abstract

Epstein-Barr virus (EBV) encodes >44 viral microRNAs (miRNAs) that are differentially expressed throughout infection, can be detected in Epstein-Barr virus (EBV)-positive tumors, and manipulate several biological processes, including cell proliferation, apoptosis, and immune responses. Here, we show that EBV BHRF1-2 miRNAs block NF-κB activation following treatment with proinflammatory cytokines, specifically interleukin-1β (IL-1β). Analysis of EBV PAR-CLIP miRNA targetome data sets combined with pathway analysis revealed multiple BHRF1-2 miRNA targets involved in interleukin signaling pathways. By further analyzing changes in cellular gene expression patterns, we identified the IL-1 receptor 1 (IL1R1) as a direct target of miR-BHRF1-2-5p. Targeting the IL1R1 3' untranslated region (UTR) by EBV miR-BHRF1-2-5p was confirmed using 3'-UTR luciferase reporter assays and Western blot assays. Manipulation of EBV BHRF1-2 miRNA activity in latently infected B cells altered steady-state cytokine levels and disrupted IL-1β responsiveness. These studies demonstrate functionally relevant BHRF1-2 miRNA interactions during EBV infection, which is an important step in understanding their roles in pathogenesis. IL-1 signaling plays an important role in inflammation and early activation of host innate immune responses following virus infection. Here, we demonstrate that a viral miRNA downregulates the IL-1 receptor 1 during EBV infection, which consequently alters the responsiveness of cells to IL-1 stimuli and changes the cytokine expression levels within infected cell populations. We postulate that this viral miRNA activity not only disrupts IL-1 autocrine and paracrine signaling loops that can alert effector cells to sites of infection but also provides a survival advantage by dampening excessive inflammation that may be detrimental to the infected cell.

Role of Viral and Host microRNAs in Immune Regulation of Epstein-Barr Virus-Associated Diseases

“…During lytic infection, miR-BHRF1-2-5p targets the 3 ′ untranslated region of the interleukin-1 receptor 1 (IL-1R1) and suppresses IL-1 signaling (33). miR-BHRF1-3-5p in EBV-infected B cells downregulates C-X-C motif chemokine 11 (CXCL-11) that is a downstream effector in interferon gamma (IFN-γ) signaling (35).…”

Implication of viral microRNAs in the genesis and diagnosis of Epstein‑Barr virus‑associated tumors (Review)

“…Signaling of interleukin-1 (IL-1) serves an important role in inflammation and early activation of the antiviral innate immune response. EBV-encoded miRs have been identified to target the 3'-UTR of IL-1 receptor 1 mRNA, as confirmed by 3'-UTR luciferase reporter assays (66). This viral miR activity disrupts IL-1 autocrine and paracrine signaling loops and provides a survival advantage by dampening excessive inflammation that is detrimental to the infected cell.…”

Epstein barr virus encodes miRNAs to assist host immune escape

“…When EBV virus invades, IL-1 signaling pathway plays an important role in triggering an inflammatory response and host innate immune response [73]. Skinner, C.M., et al that EBV miR-BHRF2-5p can directly target The IL-1 receptor (L1R1), the activation of IL-Lβ-induced NF-kB, and inhibits activation of host lymphocytes and immune responses [74]. IL-6 can promote the proliferation of B cells and T cells, stimulate the activation of CTL cells, and participate in the inflammatory response [75], while EBV miR-BART6-3p can target IL-6 receptors and inhibit lymphocyte immune activation [76].…”