Epstein-Barr Virus Large Tegument Protein BPLF1 Contributes to Innate Immune Evasion through Interference with Toll-Like Receptor Signaling

Abstract

Viral infection triggers an early host response through activation of pattern recognition receptors, including Toll-like receptors (TLR). TLR signaling cascades induce production of type I interferons and proinflammatory cytokines involved in establishing an anti-viral state as well as in orchestrating ensuing adaptive immunity. To allow infection, replication, and persistence, (herpes)viruses employ ingenious strategies to evade host immunity. The human gamma-herpesvirus Epstein-Barr virus (EBV) is a large, enveloped DNA virus persistently carried by more than 90% of adults worldwide. It is the causative agent of infectious mononucleosis and is associated with several malignant tumors. EBV activates TLRs, including TLR2, TLR3, and TLR9. Interestingly, both the expression of and signaling by TLRs is attenuated during productive EBV infection. Ubiquitination plays an important role in regulating TLR signaling and is controlled by ubiquitin ligases and deubiquitinases (DUBs). The EBV genome encodes three proteins reported to exert in vitro deubiquitinase activity. Using active site-directed probes, we show that one of these putative DUBs, the conserved herpesvirus large tegument protein BPLF1, acts as a functional DUB in EBV-producing B cells. The BPLF1 enzyme is expressed during the late phase of lytic EBV infection and is incorporated into viral particles. The N-terminal part of the large BPLF1 protein contains the catalytic site for DUB activity and suppresses TLR-mediated activation of NF-κB at, or downstream of, the TRAF6 signaling intermediate. A catalytically inactive mutant of this EBV protein did not reduce NF-κB activation, indicating that DUB activity is essential for attenuating TLR signal transduction. Our combined results show that EBV employs deubiquitination of signaling intermediates in the TLR cascade as a mechanism to counteract innate anti-viral immunity of infected hosts.

Epstein-Barr virus LMP2A suppresses MHC class II expression by regulating the B-cell transcription factors E47 and PU.1

“…EBV uses various strategies to attenuate the first line of innate immunity; for example, latent membrane protein 1 (LMP1) negatively regulates the expression of the important sensor Toll-like receptor 9, 2 B-cell receptor F1 (BCRF1)-encoded viral interleukin-10 inhibits interferon production, 3 and the tegument protein BPLF1 blocks Toll-like receptor signaling. 4 In counteracting the adaptive immune response, EBV interferes with the major histocompatibility complex (MHC) class I and II antigen presentations, which are the key factors for adaptive immunity. MHC antigens are critical in the cellular immune response, which is important for viral clearance.…”

Immune Evasion by Epstein-Barr Virus

“…BGLF5's additional RNase function utilizes the same catalytic site as its DNase activity, yet the substrate-binding site appears only partly shared by DNA and RNA substrates (Horst et al 2012). The promiscuous RNA degradation induced by EBV BGLF5 can affect immunologically relevant proteins, including TLR2 and TLR9 that are capable of sensing EBV infection (Gaudreault et al 2007;van Gent et al 2011van Gent et al , 2015. The observation that BGLF5 did not downregulate TLR4, a TLR not reported to contribute to EBV detection, suggests some Fig.…”

Study the Cross-talk Between Hepatitis B Virus Infection and Interferon Regulatory Factors in Liver Transplant Patients

“…The presence of HBV immunologic markers were analyzed in plasma sample of all patients using the enzyme-linked immunosorbent assay (ELISA) technique prior to transplantation. The HBV recipients understudy were divided into rejection (20) and non-rejection (26) patient groups, based on the pathological result. A healthy control group including 13 subjects was enrolled.…”

“…ORF47 (open reading frame 47) in varicella-zoster virus (VZV) inhibited TBK1 by atypical phosphorylation of IRF3 (19). Deubiquitinase activity of BPLF-1 protein in Epstein-bar virus (EBV) degrades IKKα to inhibit IRF7 activity (20). The BGLF4 in EBV bound directly to IRF3 and inhibited the interaction of IRF3 with target promoters (21).…”