The TLR3/IRF1/Type III IFN Axis Facilitates Antiviral Responses against Enterovirus Infections in the Intestine
ABSTRACT Enteroviruses infect gastrointestinal epithelium cells, cause multiple human diseases, and present public health risks worldwide. However, the mechanisms underlying host immune responses in intestinal mucosa against the early enterovirus infections remain elusive. Here, we showed that human...
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| Format: | Article |
| Language: | English |
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American Society for Microbiology
2020-12-01
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| Series: | mBio |
| Subjects: | |
| Online Access: | https://journals.asm.org/doi/10.1128/mBio.02540-20 |
| _version_ | 1818901029250400256 |
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| author | Rui Su Muhammad Adnan Shereen Xiaofeng Zeng Yicong Liang Wen Li Zhihui Ruan Yongkui Li Weiyong Liu Yingle Liu Kailang Wu Zhen Luo Jianguo Wu |
| author_facet | Rui Su Muhammad Adnan Shereen Xiaofeng Zeng Yicong Liang Wen Li Zhihui Ruan Yongkui Li Weiyong Liu Yingle Liu Kailang Wu Zhen Luo Jianguo Wu |
| author_sort | Rui Su |
| collection | DOAJ |
| description | ABSTRACT Enteroviruses infect gastrointestinal epithelium cells, cause multiple human diseases, and present public health risks worldwide. However, the mechanisms underlying host immune responses in intestinal mucosa against the early enterovirus infections remain elusive. Here, we showed that human enteroviruses including enterovirus 71 (EV71), coxsackievirus B3 (CVB3), and poliovirus 1 (PV1) predominantly induce type III interferons (IFN-λ1 and IFN-λ2/3), rather than type I interferons (IFN-α and IFN-β), in cultured human normal and cancerous intestine epithelial cells (IECs), mouse intestine tissues, and human clinical intestine specimens. Mechanistic studies demonstrated that IFN-λ production is induced upon enterovirus infection through the Toll-like receptor 3/interferon regulatory factor 1 (TLR3/IRF1) signaling pathway in IECs. In turn, the supplementation of IFN-λ subsequently induces intrinsically antiviral responses against enterovirus replication. Notably, intraperitoneal injection in neonatal C57BL/6J mice with mouse recombinant IFN-λ2 protein represses EV71 replication and protects mice from viral lethal effects. Altogether, these results revealed a distinct mechanism by which the host elicited immune responses against enterovirus infections in intestine through activating the TLR3/IRF1/type III IFN axis. The new findings would provide an antiviral strategy for the prevention and treatment of enterovirus infections and associated diseases. IMPORTANCE Enterovirus infections are significant sources of human diseases and public health risks worldwide, but little is known about the mechanism of innate immune response in host intestine epithelial surface during the viral replication. We reported the epithelial immune response in cultured human normal and cancerous cells (IECs), mouse tissues, and human clinical intestine specimens following infection with enterovirus 71. The results mechanistically revealed type III interferons (IFN-λ1 and IFN-λ2/3), rather than type I interferons (IFN-α and IFN-β), as the dominant production through TLR3/IRF1 signaling upon multiple human enterovirus infection, including enterovirus 71 (EV71), coxsackievirus B3 (CVB3), and poliovirus 1 (PV1). IFN-λ subsequently induced antiviral activity against enterovirus replication in vitro and in vivo. These studies uncovered the role of the novel process of type III IFN production involved in the TLR3/IRF1 pathway in host intestine upon enterovirus infection, which highlighted a regulatory manner of antiviral defense in intestine during enterovirus infection. |
| first_indexed | 2024-12-19T20:13:15Z |
| format | Article |
| id | doaj.art-aec7835a26aa4a9ea859fe6030be6088 |
| institution | Directory Open Access Journal |
| issn | 2150-7511 |
| language | English |
| last_indexed | 2024-12-19T20:13:15Z |
| publishDate | 2020-12-01 |
| publisher | American Society for Microbiology |
| record_format | Article |
| series | mBio |
| spelling | doaj.art-aec7835a26aa4a9ea859fe6030be60882022-12-21T20:07:15ZengAmerican Society for MicrobiologymBio2150-75112020-12-0111610.1128/mBio.02540-20The TLR3/IRF1/Type III IFN Axis Facilitates Antiviral Responses against Enterovirus Infections in the IntestineRui Su0Muhammad Adnan Shereen1Xiaofeng Zeng2Yicong Liang3Wen Li4Zhihui Ruan5Yongkui Li6Weiyong Liu7Yingle Liu8Kailang Wu9Zhen Luo10Jianguo Wu11State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan, ChinaState Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan, ChinaSchool of Forensic Medicine, Kunming Medical University, Kunming, ChinaGuangdong Provincial Key Laboratory of Virology, Institute of Medical Microbiology, Jinan University, Guangzhou, ChinaState Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan, ChinaGuangdong Provincial Key Laboratory of Virology, Institute of Medical Microbiology, Jinan University, Guangzhou, ChinaGuangdong Provincial Key Laboratory of Virology, Institute of Medical Microbiology, Jinan University, Guangzhou, ChinaState Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan, ChinaState Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan, ChinaState Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan, ChinaGuangdong Provincial Key Laboratory of Virology, Institute of Medical Microbiology, Jinan University, Guangzhou, ChinaState Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan, ChinaABSTRACT Enteroviruses infect gastrointestinal epithelium cells, cause multiple human diseases, and present public health risks worldwide. However, the mechanisms underlying host immune responses in intestinal mucosa against the early enterovirus infections remain elusive. Here, we showed that human enteroviruses including enterovirus 71 (EV71), coxsackievirus B3 (CVB3), and poliovirus 1 (PV1) predominantly induce type III interferons (IFN-λ1 and IFN-λ2/3), rather than type I interferons (IFN-α and IFN-β), in cultured human normal and cancerous intestine epithelial cells (IECs), mouse intestine tissues, and human clinical intestine specimens. Mechanistic studies demonstrated that IFN-λ production is induced upon enterovirus infection through the Toll-like receptor 3/interferon regulatory factor 1 (TLR3/IRF1) signaling pathway in IECs. In turn, the supplementation of IFN-λ subsequently induces intrinsically antiviral responses against enterovirus replication. Notably, intraperitoneal injection in neonatal C57BL/6J mice with mouse recombinant IFN-λ2 protein represses EV71 replication and protects mice from viral lethal effects. Altogether, these results revealed a distinct mechanism by which the host elicited immune responses against enterovirus infections in intestine through activating the TLR3/IRF1/type III IFN axis. The new findings would provide an antiviral strategy for the prevention and treatment of enterovirus infections and associated diseases. IMPORTANCE Enterovirus infections are significant sources of human diseases and public health risks worldwide, but little is known about the mechanism of innate immune response in host intestine epithelial surface during the viral replication. We reported the epithelial immune response in cultured human normal and cancerous cells (IECs), mouse tissues, and human clinical intestine specimens following infection with enterovirus 71. The results mechanistically revealed type III interferons (IFN-λ1 and IFN-λ2/3), rather than type I interferons (IFN-α and IFN-β), as the dominant production through TLR3/IRF1 signaling upon multiple human enterovirus infection, including enterovirus 71 (EV71), coxsackievirus B3 (CVB3), and poliovirus 1 (PV1). IFN-λ subsequently induced antiviral activity against enterovirus replication in vitro and in vivo. These studies uncovered the role of the novel process of type III IFN production involved in the TLR3/IRF1 pathway in host intestine upon enterovirus infection, which highlighted a regulatory manner of antiviral defense in intestine during enterovirus infection.https://journals.asm.org/doi/10.1128/mBio.02540-20enterovirustype III interferonsintestine epithelial cellsToll-like receptor 3interferon regulatory factor 1coxsackievirus B3 |
| spellingShingle | Rui Su Muhammad Adnan Shereen Xiaofeng Zeng Yicong Liang Wen Li Zhihui Ruan Yongkui Li Weiyong Liu Yingle Liu Kailang Wu Zhen Luo Jianguo Wu The TLR3/IRF1/Type III IFN Axis Facilitates Antiviral Responses against Enterovirus Infections in the Intestine mBio enterovirus type III interferons intestine epithelial cells Toll-like receptor 3 interferon regulatory factor 1 coxsackievirus B3 |
| title | The TLR3/IRF1/Type III IFN Axis Facilitates Antiviral Responses against Enterovirus Infections in the Intestine |
| title_full | The TLR3/IRF1/Type III IFN Axis Facilitates Antiviral Responses against Enterovirus Infections in the Intestine |
| title_fullStr | The TLR3/IRF1/Type III IFN Axis Facilitates Antiviral Responses against Enterovirus Infections in the Intestine |
| title_full_unstemmed | The TLR3/IRF1/Type III IFN Axis Facilitates Antiviral Responses against Enterovirus Infections in the Intestine |
| title_short | The TLR3/IRF1/Type III IFN Axis Facilitates Antiviral Responses against Enterovirus Infections in the Intestine |
| title_sort | tlr3 irf1 type iii ifn axis facilitates antiviral responses against enterovirus infections in the intestine |
| topic | enterovirus type III interferons intestine epithelial cells Toll-like receptor 3 interferon regulatory factor 1 coxsackievirus B3 |
| url | https://journals.asm.org/doi/10.1128/mBio.02540-20 |
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