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

English version

Autoři: Kai Li ^aff001; Yongzhen Liu ^aff001; Zengkun Xu ^aff001; Yu Zhang ^aff001; Dan Luo ^aff001; Yulong Gao ^aff001; Yingjuan Qian ^aff002; Chenyi Bao ^aff002; Changjun Liu ^aff001; Yanping Zhang ^aff001; Xiaole Qi ^aff001; Hongyu Cui ^aff001; Yongqiang Wang ^aff001; Li Gao ^aff001; Xiaomei Wang ^aff001
Působiště autorů: Avian Immunosuppressive Diseases Division, State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin, China ^aff001; MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, China ^aff002
Vyšlo v časopise: Avian oncogenic herpesvirus antagonizes the cGAS-STING DNA-sensing pathway to mediate immune evasion. PLoS Pathog 15(9): e32767. doi:10.1371/journal.ppat.1007999
Kategorie: Research Article
doi: https://doi.org/10.1371/journal.ppat.1007999

Souhrn

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.

Klíčová slova:

Biology and life sciences – Organisms – Eukaryota – Animals – Vertebrates – Amniotes – Birds – Fowl – Gamefowl – Chickens – Poultry – Molecular biology – Molecular biology techniques – DNA construction – Plasmid construction – Microbiology – Virology – Viral replication – Computational biology – Genetics – Genomics – Genome analysis – Gene prediction – Biochemistry – Enzymology – Enzymes – Oxidoreductases – Luciferase – Proteins – Bioengineering – Biotechnology – Genetic engineering – Plasmid vectors – Research and analysis methods – Medicine and health sciences – Oncology – Carcinogenesis – Immunology – Immune response – Engineering and technology

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