Hide‐and‐seek by Epstein‐Barr virus: evasion of innate immunity

Abstract

The human herpesvirus Epstein-Barr virus (EBV) is a large DNA virus that infects over 90% of the adult world population. While often present without obvious symptoms, EBV is causally involved in infectious mononucleosis and various malignancies of lymphoid and epithelial origin. The host innate immune system poses a first barrier against invading pathogens, inducing direct antiviral responses and orchestrating adaptive immunity. EBV establishes lifelong infections in immunocompetent hosts, withstanding elimination by the host immune system. Whereas many evasion mechanisms have been identified for the adaptive immune system, our knowledge on innate evasion strategies remains more obscure. This thesis describes novel strategies employed by EBV to evade recognition and elimination by the innate immune system. We found that the EBV alkaline exonuclease BGLF5 destabilizes cellular mRNAs, thereby decreasing expression of proteins relevant in the initial detection of EBV particles, e.g. Toll-like receptor (TLR) 2 and TLR9. In addition, the conserved herpesvirus-encoded deubiquitinase, BPLF1 in EBV, targets several intermediates of the TLR signaling pathway to inhibit NF-κB mediated induction of proinflammatory mediators. Additionally, we show that EBV expresses a viral microRNA that interferes with the type I IFN-induced signaling pathway and reduces induction of antiviral interferon-stimulated genes.

The work described in this thesis shows that EBV has adopted a wide range of strategies to compromise host innate immune responses at various levels using viral proteins as well as miRNAs. These evasion mechanisms may contribute to the development of EBV-associated malignancies. Improving our insights into the interactions between EBV and the human host may thus aid in the development of novel strategies to combat EBV infections and diseases associated with this oncogenic herpesvirus. Furthermore, it increases our knowledge of the cellular pathways that are involved in antiviral defenses.