Epstein-Barr Virus and Innate Immunity: Friends or Foes?

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.

Keywords: EBV; Epstein–Barr virus; caspase; inflammasome; interferon.

Figure 1

Epstein–Barr virus (EBV) perturbation of Toll-like receptor (TLR), RIG-I-like receptor (RLR), and cyclic GMP-AMP (cGAMP) synthase (cGAS) signaling. Signaling through TLR (left part of the diagram), RIG-I (right part), and cGAS (central part) is positively and negatively regulated by EBV proteins and RNAs. On the one hand, EBV proteins and RNAs inhibit these pathways to suppress antiviral interferons (IFN) and cytokine production to facilitate viral infection (highlighted in red). On the other hand, they can also activate some of these pathways to promote cellular growth and survival (shown in green). See text for further details.

Figure 2

EBV perturbation of NOD-like receptor (NLR) and AIM2-like receptors (ALR) signaling. On the one hand, EBV suppresses these pathways through its viral proteins and RNAs to circumvent their antiviral effects (shown in red). On the other hand, EBV can also activate some of these pathways to cause pathogenic inflammation and to facilitate viral spreading and infection (highlighted in green). See text for further details.

Figure 3

EBV perturbation of IFN signaling. EBV proteins and RNAs suppress Type I and Type II IFN signaling to facilitate EBV infection, maintenance, and reactivation in the infected cells (molecules depicted in red). Some of them can also activate STAT signaling, including STAT3, to promote cell proliferation, survival, and immune evasion (molecules depicted in green). STAT3RE: STAT3 response element. See text for further details.

Figure 4

Delicate balance of proviral and antiviral roles of caspases in EBV biology. On the one hand, activation of caspases leads to programmed cell death such as apoptosis and pyroptosis, which limit the spread of virus. On the other hand, activated caspases can cleave host restriction factors such as PIAS1, TBK1/IKKε-IRF3, and KAP1 and the viral factor BPLF1 to facilitate EBV lytic reactivation. The viral inhibitors of caspase signaling are depicted in red, and the activators are depicted in green. See text for further details.