Abstract
Epstein–Barr virus (EBV) successfully persists in the vast majority of adults but causes lymphoid and epithelial malignancies in a small fraction of latently infected individuals. Innate immunity is the first-line antiviral defense, which EBV has to evade in favor of its own replication and infection. EBV uses multiple strategies to perturb innate immune signaling pathways activated by Toll-like, RIG-I-like, NOD-like, and AIM2-like receptors as well as cyclic GMP-AMP synthase. EBV also counteracts interferon production and signaling, including TBK1-IRF3 and JAK-STAT pathways. However, activation of innate immunity also triggers pro-inflammatory response and proteolytic cleavage of caspases, both of which exhibit proviral activity under some circumstances. Pathogenic inflammation also contributes to EBV oncogenesis. EBV activates NFκB signaling and induces pro-inflammatory cytokines. Through differential modulation of the proviral and antiviral roles of caspases and other host factors at different stages of infection, EBV usurps cellular programs for death and inflammation to its own benefits. The outcome of EBV infection is governed by a delicate interplay between innate immunity and EBV. A better understanding of this interplay will instruct prevention and intervention of EBV-associated cancers.
Highlights
Epstein–Barr Virus (EBV), known as human herpesvirus 4 (HHV-4), is a member of the subfamily of Gammaherpesvirinae, which includes Kaposi sarcoma-associated herpesvirus (KSHV)
It will be of great interest to see whether their induction might be influential in different latency states of EBV and in EBV oncogenesis
EBV proteins capable of inhibiting IFN signaling such as Zta, BGLF4, and LMP1 necessarily affect the expression of interferon-stimulated genes (ISGs), thereby preventing the establishment of an antiviral state and promoting viral replication
Summary
Epstein–Barr Virus (EBV), known as human herpesvirus 4 (HHV-4), is a member of the subfamily of Gammaherpesvirinae, which includes Kaposi sarcoma-associated herpesvirus (KSHV). Lytic reactivation can be induced by the expression of viral BZLF1 protein, known as Zta, leading to virion production and the spread of EBV infection. To evade innate immune sensing and the consequent activation of antiviral cascades, EBV has evolved multiple effective countermeasures These can occur at different pathways and steps ranging from recognition by cell surface, endosomal, and intracellular sensors to IFN production and signaling. This interplay between EBV and innate immunity is influential to the outcome of infection. We will discuss the current knowledge of countermeasures adopted by EBV to perturb innate immune response with a focus on IFN production and signaling, inflammasome assembly, programmed cell death, and caspase activation
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