Suppression of IFN-β production by Epstein-Barr virus lytic transactivator Zta

Abstract

 As one of the most prevalent human virus, Epstein-Barr virus (EBV)is well-known for its association with various types of disease during its life cycle, namely, primary infection, latent infection and reactivation. More importantly, EBV is able to modulate and thus evade from the host innate immunity during each of these infection stages. How this can be achieved is not well understood. Individual EBV proteins have been demonstrated to dampen host innate immunity, particularly the production of the potent antiviral cytokine, type I IFNs. Unfortunately, these studies mostly adopted a candidate approach and therefore unable to delineate the full picture of how different EBV proteins cooperate spatially and temporally to inhibit the production of type I IFNs. In this study, EBV primary infection was demonstrated to inhibit IFN-β production. A dual-luciferase screen of EBV expression library on their ability to suppress type I IFNs production was also documented. EBV lytic transactivator Zta was identified as a strong candidate of EBV-encoded IFN-β production antagonist and was shown to display dose-dependent inhibitory effect. Using different downstream stimulators, Zta was indicated to act on the level of IRF3 in the context of IFN-β production inhibition. However, Zta did not affect IRF3transcript and protein level. Instead, phosphorylation and subsequent dimerization of IRF3 induced by upstream stimulants was dampened by Zta expression. Co-immunoprecipitation study revealed no physical interaction between Zta andIRF3. Last but not least, by studying the ability of inhibiting IFN-β production by different Zta mutants, the transactivation ability of Zta was demonstrated to be indispensable for optimal Zta-mediated IRF3 inhibition. This study elucidated a novel mechanism of host innate immunity suppression by EBV and shed light on the importance of suppressing the host innate immunity at the beginning of EBV lytic replication and reactivation.