Toll-Like Receptor 3 Is Involved in Detection of Enterovirus A71 Infection and Targeted by Viral 2A Protease
Enterovirus A71 (EV-A71) has emerged as a major pathogen causing hand, foot, and mouth disease, as well as neurological disorders. The host immune response affects the outcomes of EV-A71 infection, leading to either resolution or disease progression. However, the mechanisms of how the mammalian inna...
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| Format: | Article |
| Language: | English |
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MDPI AG
2018-12-01
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| Series: | Viruses |
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| Online Access: | https://www.mdpi.com/1999-4915/10/12/689 |
| _version_ | 1818333976308219904 |
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| author | Kuan-Ru Chen Chun-Keung Yu Szu-Hao Kung Shun-Hua Chen Chuan-Fa Chang Tzu-Chuan Ho Yi-Ping Lee Hung-Chuan Chang Lan-Yin Huang Shih-Yen Lo Jui-Chung Chang Pin Ling |
| author_facet | Kuan-Ru Chen Chun-Keung Yu Szu-Hao Kung Shun-Hua Chen Chuan-Fa Chang Tzu-Chuan Ho Yi-Ping Lee Hung-Chuan Chang Lan-Yin Huang Shih-Yen Lo Jui-Chung Chang Pin Ling |
| author_sort | Kuan-Ru Chen |
| collection | DOAJ |
| description | Enterovirus A71 (EV-A71) has emerged as a major pathogen causing hand, foot, and mouth disease, as well as neurological disorders. The host immune response affects the outcomes of EV-A71 infection, leading to either resolution or disease progression. However, the mechanisms of how the mammalian innate immune system detects EV-A71 infection to elicit antiviral immunity remain elusive. Here, we report that the Toll-like receptor 3 (TLR3) is a key viral RNA sensor for sensing EV-A71 infection to trigger antiviral immunity. Expression of TLR3 in HEK293 cells enabled the cells to sense EV-A71 infection, leading to type I, IFN-mediated antiviral immunity. Viral double-stranded RNA derived from EV-A71 infection was a key ligand for TLR3 detection. Silencing of TLR3 in mouse and human primary immune cells impaired the activation of IFN-β upon EV-A71 infection, thus reinforcing the importance of the TLR3 pathway in defending against EV-A71 infection. Our results further demonstrated that TLR3 was a target of EV-A71 infection. EV-A71 protease 2A was implicated in the downregulation of TLR3. Together, our results not only demonstrate the importance of the TLR3 pathway in response to EV-A71 infection, but also reveal the involvement of EV-A71 protease 2A in subverting TLR3-mediated antiviral defenses. |
| first_indexed | 2024-12-13T14:00:11Z |
| format | Article |
| id | doaj.art-50dbbcb37239425c98b31f214f760c15 |
| institution | Directory Open Access Journal |
| issn | 1999-4915 |
| language | English |
| last_indexed | 2024-12-13T14:00:11Z |
| publishDate | 2018-12-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Viruses |
| spelling | doaj.art-50dbbcb37239425c98b31f214f760c152022-12-21T23:42:45ZengMDPI AGViruses1999-49152018-12-01101268910.3390/v10120689v10120689Toll-Like Receptor 3 Is Involved in Detection of Enterovirus A71 Infection and Targeted by Viral 2A ProteaseKuan-Ru Chen0Chun-Keung Yu1Szu-Hao Kung2Shun-Hua Chen3Chuan-Fa Chang4Tzu-Chuan Ho5Yi-Ping Lee6Hung-Chuan Chang7Lan-Yin Huang8Shih-Yen Lo9Jui-Chung Chang10Pin Ling11Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan 70101, TaiwanInstitute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan 70101, TaiwanDepartment of Biotechnology and Laboratory Science in Medicine, National Yang Ming University, Taipei 11221, TaiwanInstitute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan 70101, TaiwanInstitute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan 70101, TaiwanInstitute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan 70101, TaiwanInstitute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan 70101, TaiwanDepartment of Microbiology and Immunology, College of Medicine, National Cheng Kung University, Tainan 70101, TaiwanDepartment of Medicine, College of Medicine, National Cheng Kung University, Tainan 70101, TaiwanDepartment of Laboratory Medicine and Biotechnology, Tzu Chi University, Hualien 97004, TaiwanDepartment of Prosthetic Dentistry, Chi-Mei Medical Center, Tainan 71004, TaiwanInstitute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan 70101, TaiwanEnterovirus A71 (EV-A71) has emerged as a major pathogen causing hand, foot, and mouth disease, as well as neurological disorders. The host immune response affects the outcomes of EV-A71 infection, leading to either resolution or disease progression. However, the mechanisms of how the mammalian innate immune system detects EV-A71 infection to elicit antiviral immunity remain elusive. Here, we report that the Toll-like receptor 3 (TLR3) is a key viral RNA sensor for sensing EV-A71 infection to trigger antiviral immunity. Expression of TLR3 in HEK293 cells enabled the cells to sense EV-A71 infection, leading to type I, IFN-mediated antiviral immunity. Viral double-stranded RNA derived from EV-A71 infection was a key ligand for TLR3 detection. Silencing of TLR3 in mouse and human primary immune cells impaired the activation of IFN-β upon EV-A71 infection, thus reinforcing the importance of the TLR3 pathway in defending against EV-A71 infection. Our results further demonstrated that TLR3 was a target of EV-A71 infection. EV-A71 protease 2A was implicated in the downregulation of TLR3. Together, our results not only demonstrate the importance of the TLR3 pathway in response to EV-A71 infection, but also reveal the involvement of EV-A71 protease 2A in subverting TLR3-mediated antiviral defenses.https://www.mdpi.com/1999-4915/10/12/689Enterovirus 71Toll-like receptor 3innate immune systemEV-A71 protease 2AType I IFN |
| spellingShingle | Kuan-Ru Chen Chun-Keung Yu Szu-Hao Kung Shun-Hua Chen Chuan-Fa Chang Tzu-Chuan Ho Yi-Ping Lee Hung-Chuan Chang Lan-Yin Huang Shih-Yen Lo Jui-Chung Chang Pin Ling Toll-Like Receptor 3 Is Involved in Detection of Enterovirus A71 Infection and Targeted by Viral 2A Protease Viruses Enterovirus 71 Toll-like receptor 3 innate immune system EV-A71 protease 2A Type I IFN |
| title | Toll-Like Receptor 3 Is Involved in Detection of Enterovirus A71 Infection and Targeted by Viral 2A Protease |
| title_full | Toll-Like Receptor 3 Is Involved in Detection of Enterovirus A71 Infection and Targeted by Viral 2A Protease |
| title_fullStr | Toll-Like Receptor 3 Is Involved in Detection of Enterovirus A71 Infection and Targeted by Viral 2A Protease |
| title_full_unstemmed | Toll-Like Receptor 3 Is Involved in Detection of Enterovirus A71 Infection and Targeted by Viral 2A Protease |
| title_short | Toll-Like Receptor 3 Is Involved in Detection of Enterovirus A71 Infection and Targeted by Viral 2A Protease |
| title_sort | toll like receptor 3 is involved in detection of enterovirus a71 infection and targeted by viral 2a protease |
| topic | Enterovirus 71 Toll-like receptor 3 innate immune system EV-A71 protease 2A Type I IFN |
| url | https://www.mdpi.com/1999-4915/10/12/689 |
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