Avian oncogenic herpesvirus antagonizes the cGAS-STING DNA-sensing pathway to mediate immune evasion.

Kai Li,Yulong Gao,Xiaole Qi,Chenyi Bao,Yongzhen Liu,Dan Luo,Changjun Liu,Yu Zhang,Li Gao,Hongyu Cui,Xiaomei Wang,Zengkun Xu,Yongqiang Wang,Yanping Zhang,Yingjuan Qian,Pinghui Feng

doi:10.1371/journal.ppat.1007999

Abstract

The cellular DNA sensor cGMP-AMP synthase (cGAS) detects cytosolic viral DNA via the stimulator of interferon genes (STING) to initiate innate antiviral response. Herpesviruses are known to target key immune signaling pathways to persist in an immune-competent host. Marek’s disease virus (MDV), a highly pathogenic and oncogenic herpesvirus of chickens, can antagonize host innate immune responses to achieve persistent infection. With a functional screen, we identified five MDV proteins that blocked beta interferon (IFN-β) induction downstream of the cGAS-STING pathway. Specifically, the MDV major oncoprotein Meq impeded the recruitment of TANK-binding kinase 1 and IFN regulatory factor 7 (IRF7) to the STING complex, thereby inhibiting IRF7 activation and IFN-β induction. Meq overexpression markedly reduced antiviral responses stimulated by cytosolic DNA, whereas knockdown of Meq heightened MDV-triggered induction of IFN-β and downstream antiviral genes. Moreover, Meq-deficient MDV induced more IFN-β production than wild-type MDV. Meq-deficient MDV also triggered a more robust CD8+ T cell response than wild-type MDV. As such, the Meq-deficient MDV was highly attenuated in replication and lymphoma induction compared to wild-type MDV. Taken together, these results revealed that MDV evades the cGAS-STING DNA sensing pathway, which underpins the efficient replication and oncogenesis. These findings improve our understanding of the virus-host interaction in MDV-induced lymphoma and may contribute to the development of novel vaccines against MDV infection.

Highlights

Herpesviruses are important pathogens associated with a wide range of diseases in humans and animals
Marek’s disease virus (MDV) is an avian oncogenic herpesvirus that causes a fatal disease in poultry worldwide
Consistent with the inhibition of IFN-β induction, various MDV proteins were expressed during the late phase of viral infection (Fig 1A), suggesting that these viral proteins might contribute to the modulation of the IFN-β response during viral infection

Summary

Introduction

Herpesviruses are important pathogens associated with a wide range of diseases in humans and animals. Marek’s disease virus (MDV) constitutes a highly pathogenic and oncogenic herpesvirus of chickens [1]. As a disease that affects poultry worldwide with economic implications, Marek’s disease (MD) has contributed substantially to our understanding of herpesvirus-associated oncogenicity [2]. MD lymphomas exhibit many biological parallels with the lymphoid neoplasias associated with human herpesviruses such as Epstein-Barr virus (EBV) [3]. Despite the success of vaccination in controlling MD over the last 40 years, continuous evolution of virulence among MDV strains remains a major challenge for sustainable control of this disease [4]. A better understanding of MDV-host interactions is, important to elucidate the events in oncogenesis and develop more effective vaccines to combat infection

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