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

PLoS Pathog. 2019 Sep 20;15(9):e1007999. doi: 10.1371/journal.ppat.1007999. eCollection 2019 Sep.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Avian Proteins / metabolism
  • Carcinogenesis
  • Chickens
  • DNA, Viral / immunology
  • Ducks
  • Herpesvirus 2, Gallid / immunology*
  • Herpesvirus 2, Gallid / pathogenicity*
  • Herpesvirus 2, Gallid / physiology
  • Host Microbial Interactions / immunology
  • Immune Evasion*
  • Immunity, Innate
  • Interferon Regulatory Factor-7 / metabolism
  • Interferon-beta / metabolism
  • Marek Disease / immunology*
  • Marek Disease / metabolism
  • Marek Disease / virology*
  • Models, Immunological
  • Nucleotidyltransferases / metabolism
  • Oncogene Proteins, Viral / immunology
  • Protein-Serine-Threonine Kinases / metabolism
  • Signal Transduction
  • Viral Proteins / immunology
  • Virus Replication

Substances

  • Avian Proteins
  • DNA, Viral
  • Interferon Regulatory Factor-7
  • Oncogene Proteins, Viral
  • Viral Proteins
  • Interferon-beta
  • Protein-Serine-Threonine Kinases
  • Nucleotidyltransferases

Grant support

This research was supported by a grant from the National Key Research and Development Program of China (2016YFE0203200) (XQ), National Natural Science Foundation of China (31600127) (KL), Natural Science Foundation of Heilongjiang, China (QC2016042) (KL) and Modern Agroindustry Technology Research System in China (nycytx-42-G3-01) (XW). The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.