Avian oncogenic herpesvirus antagonizes the cGAS-STING DNA-sensing pathway to mediate immune evasion.
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),...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2019-09-01
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| Series: | PLoS Pathogens |
| Online Access: | https://doi.org/10.1371/journal.ppat.1007999 |
| _version_ | 1818361156558913536 |
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| author | Kai Li Yongzhen Liu Zengkun Xu Yu Zhang Dan Luo Yulong Gao Yingjuan Qian Chenyi Bao Changjun Liu Yanping Zhang Xiaole Qi Hongyu Cui Yongqiang Wang Li Gao Xiaomei Wang |
| author_facet | Kai Li Yongzhen Liu Zengkun Xu Yu Zhang Dan Luo Yulong Gao Yingjuan Qian Chenyi Bao Changjun Liu Yanping Zhang Xiaole Qi Hongyu Cui Yongqiang Wang Li Gao Xiaomei Wang |
| author_sort | Kai Li |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-13T21:12:12Z |
| format | Article |
| id | doaj.art-94cfb644053b4cebabc81a048ae11e21 |
| institution | Directory Open Access Journal |
| issn | 1553-7366 1553-7374 |
| language | English |
| last_indexed | 2024-12-13T21:12:12Z |
| publishDate | 2019-09-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Pathogens |
| spelling | doaj.art-94cfb644053b4cebabc81a048ae11e212022-12-21T23:31:19ZengPublic Library of Science (PLoS)PLoS Pathogens1553-73661553-73742019-09-01159e100799910.1371/journal.ppat.1007999Avian oncogenic herpesvirus antagonizes the cGAS-STING DNA-sensing pathway to mediate immune evasion.Kai LiYongzhen LiuZengkun XuYu ZhangDan LuoYulong GaoYingjuan QianChenyi BaoChangjun LiuYanping ZhangXiaole QiHongyu CuiYongqiang WangLi GaoXiaomei WangThe 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.https://doi.org/10.1371/journal.ppat.1007999 |
| spellingShingle | Kai Li Yongzhen Liu Zengkun Xu Yu Zhang Dan Luo Yulong Gao Yingjuan Qian Chenyi Bao Changjun Liu Yanping Zhang Xiaole Qi Hongyu Cui Yongqiang Wang Li Gao Xiaomei Wang Avian oncogenic herpesvirus antagonizes the cGAS-STING DNA-sensing pathway to mediate immune evasion. PLoS Pathogens |
| title | Avian oncogenic herpesvirus antagonizes the cGAS-STING DNA-sensing pathway to mediate immune evasion. |
| title_full | Avian oncogenic herpesvirus antagonizes the cGAS-STING DNA-sensing pathway to mediate immune evasion. |
| title_fullStr | Avian oncogenic herpesvirus antagonizes the cGAS-STING DNA-sensing pathway to mediate immune evasion. |
| title_full_unstemmed | Avian oncogenic herpesvirus antagonizes the cGAS-STING DNA-sensing pathway to mediate immune evasion. |
| title_short | Avian oncogenic herpesvirus antagonizes the cGAS-STING DNA-sensing pathway to mediate immune evasion. |
| title_sort | avian oncogenic herpesvirus antagonizes the cgas sting dna sensing pathway to mediate immune evasion |
| url | https://doi.org/10.1371/journal.ppat.1007999 |
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