Innate Immune Recognition of EBV

Abstract

The ability of Epstein-Barr virus (EBV) to establish latency despite specific immune responses and to successfully persist lifelong in the human host shows that EBV has developed powerful strategies and mechanisms to exploit, evade, abolish, or downsize otherwise effective immune responses to ensure its own survival. This chapter focuses on current knowledge on innate immune responses against EBV and its evasion strategies for own benefit and summarizes the questions that remain to be tackled. Innate immune reactions against EBV originate both from the main target cells of EBV and from nontarget cells, which are elements of the innate immune system. Thus, we structured our review accordingly but with a particular focus on the innate recognition of EBV in its two stages in its life cycle, latent state and lytic replication. Specifically, we discuss (I) innate sensing and resulting innate immune responses against EBV by its main target cells, focusing on (i) EBV transmission between epithelial cells and B cells and their life cycle stages; and (ii) elements of innate immunity in EBV's target cells. Further, we debate (II) the innate recognition and resulting innate immune responses against EBV by cells other than the main target cells, focusing on (iii) myeloid cells: dendritic cells, monocytes, macrophages, and neutrophil granulocytes; and (iv) natural killer cells. Finally, we address (III) how EBV counteracts or exploits innate immunity in its latent and lytic life cycle stages, concentrating on (v) TLRs; (vi) EBERs; and (vii) microRNAs.

EBV up-regulates PD-L1 on the surface of primary monocytes by increasing ROS and activating TLR signaling and STAT3

“…Human monocytes express several TLRs reported to sense EBV products including TLR 8, whose expression can be strongly up‐regulated by EBV infection . TLR signaling has been shown to affect PD‐L1 expression, thus we next investigated whether the inhibition of TLR signaling by IRAK1/4 inhibitor could counteract such immune suppressive effect induced by EBV.…”

“…It has been reported that it down‐regulated TLR9 or up‐regulated TLR 7 in B cells, whereas in monocytes, it activated and increased the expression of TLR 8 . TLRs represent a family of PRRs widely expressed among the immune system cells, which plays an essential role in pathogen recognition; therefore, the modulation of TLR expression or activation represent a possible strategy to impair immune recognition . Interestingly, in addition to immune stimulating functions, TLR signaling may also mediate immune suppressive effects, including the up‐regulation of PD‐L1 .…”

“…This suggests the occurrence of lifelong iron arm between the virus and the host immune system. To win this battle, EBV may down‐regulate the surface MHC molecules to impair viral antigen presentation, reduce monocyte differentiation into DCs, alter cytokine release, and up‐regulate the expression of immune suppressive molecules such as IDO in monocyte‐derived macrophages . Programmed death ligand 1 (PD‐L1) is a membrane immune‐modulatory protein that, by interacting with Programmed death 1 (PD‐1), delivers inhibitory signals, regulating the balance between T cell activation and tolerance.…”

Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) with intracranial Epstein–Barr virus infection

“…It is reported that the main target cells of EBV are epithelial cells and B cells. [14] EBV could infect epithelial cells via apical to basolateral transcytosis. [15] Thus, the elevated EBV DNA in CSF may be due to the CNS EBV reactivation or the activated resident EBV-positive cells in the CNS by the local inflammation.…”

The Immune Response to Epstein Barr Virus and Implications for Posttransplant Lymphoproliferative Disorder

“…While the adaptive immune response to EBV has been extensively analyzed, only more recently has the role of the innate immune system (25), and natural killer (NK) cells in particular (26), been addressed. NK cells are lymphocytes of the innate immune system that possess the ability to rapidly recognize and respond to virally infected cells via cytotoxic pathways or production of immunomodulatory cytokines, hence they are viewed as an initial line of defense following infection.…”