Immune escape of avian oncogenic Marek's disease herpesvirus and antagonistic host immune responses

Abstract

Marek's disease virus (MDV) is a highly pathogenic and oncogenic alpha herpesvirus that causes Marek's disease (MD), which is one of the most important immunosuppressive and rapid-onset neoplastic diseases in poultry. The onset of MD lymphomas and other clinical diseases can be efficiently prevented by vaccination; these vaccines are heralded as the first demonstration of a successful vaccination strategy against a cancer. However, the persistent evolution of epidemic MDV strains towards greater virulence has recently resulted in frequent outbreaks of MD in vaccinated chicken flocks worldwide. Herein, we provide an overall review focusing on the discovery and identification of the strategies by which MDV evades host immunity and attacks the immune system. We have also highlighted the decrease in the immune efficacy of current MD vaccines. The prospects, strategies and new techniques for the development of efficient MD vaccines, together with the possibilities of antiviral therapy in MD, are also discussed.

Fig. 1. Schematic of the approaches by which MDV evades host surveillance and the immune response.

The key strategies and potential approaches, such as modulation of histocompatibility complexes, regulation of virus replication, viral telomeric integration, inhibition of interferon expression, manipulation of macrophages, suppression of NK-cell activation, disruption of mitochondrial dynamics, modulation of humoral immunity, and evasion of adaptive immunity, are drawn together to demonstrate the intricate interactions between viral components, host cellular proteins, and/or non-coding RNAs to counteract the host immune response. (Created with Microsoft PowerPoint).

Fig. 2. Schematic diagram of the mechanism by which MDV evades PRR-mediated type I interferon signaling pathways during viral infection.

MDVs exploit viral proteins and noncoding RNAs to evade host innate immunity by inhibiting the cGAS-STING signaling pathway, the MDA5-mediated signaling pathway and the Toll-like receptor signaling pathway. cGAS, cyclic GMP-AMP synthase; cGAMP, cyclic GMP-AMP; STING, stimulator of interferon genes; MDA5, melanoma-differentiation-associated gene 5; MAVS, mitochondrial antiviral signaling protein; TLR3, Toll-like receptor 3; TRIF, TIR-domain-containing adapter inducing interferon-β; TRAF, tumor necrosis factor receptor associated factor; TBK1, TANK-binding kinase 1; IKKε, nuclear factor kappa-B kinase epsilon; IRF, interferon regulatory transcription factor; NF-κB, nuclear factor-kappa B; NEMO, nuclear factor (NF)-kappa B essential modulator; IKKα, NF-kappa B kinase subunit alpha; IKKβ, nuclear factor kappa-B kinase beta; IκBα/β, nuclear factor kappa-B-α/β; ADAR1, adenosine deaminase acting on RNA1; DDX5, Dead-box Helicase 5. (Created with Microsoft PowerPoint).