Zika virus antagonizes interferon response in patients and disrupts RIG-I–MAVS interaction through its CARD-TM domains
Abstract Background The emerging threat to global health associated with the Zika virus (ZIKV) epidemics and its link to severe complications highlights a growing need to better understand the pathogenic mechanisms of ZIKV. Accumulating evidence for a critical role of type I interferon (IFN-I) in pr...
| Main Authors: | , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2019-06-01
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| Series: | Cell & Bioscience |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s13578-019-0308-9 |
| _version_ | 1818518132180910080 |
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| author | Yiwen Hu Xinhuai Dong Zhenjian He Yun Wu Shihao Zhang Jiajie Lin Yi Yang Jiahui Chen Shu An Yingxian Yin Zhiyong Shen Gucheng Zeng Han Tian Junchao Cai Yi Yang Hongyu Guan Jueheng Wu Mengfeng Li Xun Zhu |
| author_facet | Yiwen Hu Xinhuai Dong Zhenjian He Yun Wu Shihao Zhang Jiajie Lin Yi Yang Jiahui Chen Shu An Yingxian Yin Zhiyong Shen Gucheng Zeng Han Tian Junchao Cai Yi Yang Hongyu Guan Jueheng Wu Mengfeng Li Xun Zhu |
| author_sort | Yiwen Hu |
| collection | DOAJ |
| description | Abstract Background The emerging threat to global health associated with the Zika virus (ZIKV) epidemics and its link to severe complications highlights a growing need to better understand the pathogenic mechanisms of ZIKV. Accumulating evidence for a critical role of type I interferon (IFN-I) in protecting hosts from ZIKV infection lies in the findings that ZIKV has evolved various strategies to subvert the host defense line by counteracting the early IFN induction or subsequent IFN signaling. Yet, mechanisms underlying the counter-IFN capability of ZIKV and its proteins, which might contribute to the well-recognized broad cellular tropisms and persistence of ZIKV, remain incompletely understood. Results Using RNA sequencing-based transcriptional profiling of whole blood cells isolated from patients acutely infected by ZIKV, we found that transcriptional signature programs of antiviral interferon-stimulated genes and innate immune sensors in ZIKV-infected patients remained inactive as compared to those of healthy donors, suggesting that ZIKV was able to suppress the induction of IFN-I during the natural infection process in humans. Furthermore, by analyzing the molecular interaction in a ZIKV NS4A-overexpression system, or in the context of actual ZIKV infection, we identified that ZIKV NS4A directly bound MAVS and thereby interrupted the RIG-I/MAVS interaction through the CARD-TM domains, leading to attenuated production of IFN-I. Conclusions Our findings collectively revealed that ZIKV NS4A targeted MAVS and contributed to ZIKV immune evasion through abrogating MAVS-mediated IFN production. These findings obtained from patient studies have added new knowledge and molecular details to our understanding regarding how ZIKV mediates suppression of the IFN-I system and may provide a new basis for the future development of anti-ZIKV strategies. |
| first_indexed | 2024-12-11T01:05:52Z |
| format | Article |
| id | doaj.art-a8fe21e101e04ad4b832fb20cea7f22b |
| institution | Directory Open Access Journal |
| issn | 2045-3701 |
| language | English |
| last_indexed | 2024-12-11T01:05:52Z |
| publishDate | 2019-06-01 |
| publisher | BMC |
| record_format | Article |
| series | Cell & Bioscience |
| spelling | doaj.art-a8fe21e101e04ad4b832fb20cea7f22b2022-12-22T01:26:10ZengBMCCell & Bioscience2045-37012019-06-019111510.1186/s13578-019-0308-9Zika virus antagonizes interferon response in patients and disrupts RIG-I–MAVS interaction through its CARD-TM domainsYiwen Hu0Xinhuai Dong1Zhenjian He2Yun Wu3Shihao Zhang4Jiajie Lin5Yi Yang6Jiahui Chen7Shu An8Yingxian Yin9Zhiyong Shen10Gucheng Zeng11Han Tian12Junchao Cai13Yi Yang14Hongyu Guan15Jueheng Wu16Mengfeng Li17Xun Zhu18Key Laboratory of Tropical Disease Control (Sun Yat-sen University), Ministry of EducationKey Laboratory of Tropical Disease Control (Sun Yat-sen University), Ministry of EducationSchool of Public Health, Sun Yat-sen UniversityKey Laboratory of Tropical Disease Control (Sun Yat-sen University), Ministry of EducationDepartment of Basic Medicine, Zhongshan School of Medicine, Sun Yat-sen UniversityDepartment of Clinical Medicine, Zhongshan School of Medicine, Sun Yat-sen UniversityDepartment of Basic Medicine, Zhongshan School of Medicine, Sun Yat-sen UniversityKey Laboratory of Tropical Disease Control (Sun Yat-sen University), Ministry of EducationKey Laboratory of Tropical Disease Control (Sun Yat-sen University), Ministry of EducationGuangzhou Institute of Pediatrics, Guangzhou Women and Children’s Medical Center, Guangzhou Medical UniversityKey Laboratory of Tropical Disease Control (Sun Yat-sen University), Ministry of EducationKey Laboratory of Tropical Disease Control (Sun Yat-sen University), Ministry of EducationKey Laboratory of Tropical Disease Control (Sun Yat-sen University), Ministry of EducationKey Laboratory of Tropical Disease Control (Sun Yat-sen University), Ministry of EducationKey Laboratory of Tropical Disease Control (Sun Yat-sen University), Ministry of EducationDepartment of Endocrinology, The First Affiliated Hospital of SunYat-sen UniversityKey Laboratory of Tropical Disease Control (Sun Yat-sen University), Ministry of EducationKey Laboratory of Tropical Disease Control (Sun Yat-sen University), Ministry of EducationKey Laboratory of Tropical Disease Control (Sun Yat-sen University), Ministry of EducationAbstract Background The emerging threat to global health associated with the Zika virus (ZIKV) epidemics and its link to severe complications highlights a growing need to better understand the pathogenic mechanisms of ZIKV. Accumulating evidence for a critical role of type I interferon (IFN-I) in protecting hosts from ZIKV infection lies in the findings that ZIKV has evolved various strategies to subvert the host defense line by counteracting the early IFN induction or subsequent IFN signaling. Yet, mechanisms underlying the counter-IFN capability of ZIKV and its proteins, which might contribute to the well-recognized broad cellular tropisms and persistence of ZIKV, remain incompletely understood. Results Using RNA sequencing-based transcriptional profiling of whole blood cells isolated from patients acutely infected by ZIKV, we found that transcriptional signature programs of antiviral interferon-stimulated genes and innate immune sensors in ZIKV-infected patients remained inactive as compared to those of healthy donors, suggesting that ZIKV was able to suppress the induction of IFN-I during the natural infection process in humans. Furthermore, by analyzing the molecular interaction in a ZIKV NS4A-overexpression system, or in the context of actual ZIKV infection, we identified that ZIKV NS4A directly bound MAVS and thereby interrupted the RIG-I/MAVS interaction through the CARD-TM domains, leading to attenuated production of IFN-I. Conclusions Our findings collectively revealed that ZIKV NS4A targeted MAVS and contributed to ZIKV immune evasion through abrogating MAVS-mediated IFN production. These findings obtained from patient studies have added new knowledge and molecular details to our understanding regarding how ZIKV mediates suppression of the IFN-I system and may provide a new basis for the future development of anti-ZIKV strategies.http://link.springer.com/article/10.1186/s13578-019-0308-9Zika virusNonstructural protein 4AInterferonRIG-IMAVS |
| spellingShingle | Yiwen Hu Xinhuai Dong Zhenjian He Yun Wu Shihao Zhang Jiajie Lin Yi Yang Jiahui Chen Shu An Yingxian Yin Zhiyong Shen Gucheng Zeng Han Tian Junchao Cai Yi Yang Hongyu Guan Jueheng Wu Mengfeng Li Xun Zhu Zika virus antagonizes interferon response in patients and disrupts RIG-I–MAVS interaction through its CARD-TM domains Cell & Bioscience Zika virus Nonstructural protein 4A Interferon RIG-I MAVS |
| title | Zika virus antagonizes interferon response in patients and disrupts RIG-I–MAVS interaction through its CARD-TM domains |
| title_full | Zika virus antagonizes interferon response in patients and disrupts RIG-I–MAVS interaction through its CARD-TM domains |
| title_fullStr | Zika virus antagonizes interferon response in patients and disrupts RIG-I–MAVS interaction through its CARD-TM domains |
| title_full_unstemmed | Zika virus antagonizes interferon response in patients and disrupts RIG-I–MAVS interaction through its CARD-TM domains |
| title_short | Zika virus antagonizes interferon response in patients and disrupts RIG-I–MAVS interaction through its CARD-TM domains |
| title_sort | zika virus antagonizes interferon response in patients and disrupts rig i mavs interaction through its card tm domains |
| topic | Zika virus Nonstructural protein 4A Interferon RIG-I MAVS |
| url | http://link.springer.com/article/10.1186/s13578-019-0308-9 |
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