Negative regulation of type I interferon signaling by integrin-linked kinase permits dengue virus replication.
Dengue virus (DENV) infection can induce life-threatening dengue hemorrhagic fever/dengue shock syndrome in infected patients. DENV is a threat to global health due to its growing numbers and incidence of infection in the last 50 years. During infection, DENV expresses ten structural and nonstructur...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2023-03-01
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| Series: | PLoS Pathogens |
| Online Access: | https://doi.org/10.1371/journal.ppat.1011241 |
| _version_ | 1827968532734803968 |
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| author | Yi-Sheng Kao Li-Chiu Wang Po-Chun Chang Heng-Ming Lin Yee-Shin Lin Chia-Yi Yu Chien-Chin Chen Chiou-Feng Lin Trai-Ming Yeh Shu-Wen Wan Jen-Ren Wang Tzong-Shiann Ho Chien-Chou Chu Bo-Cheng Zhang Chih-Peng Chang |
| author_facet | Yi-Sheng Kao Li-Chiu Wang Po-Chun Chang Heng-Ming Lin Yee-Shin Lin Chia-Yi Yu Chien-Chin Chen Chiou-Feng Lin Trai-Ming Yeh Shu-Wen Wan Jen-Ren Wang Tzong-Shiann Ho Chien-Chou Chu Bo-Cheng Zhang Chih-Peng Chang |
| author_sort | Yi-Sheng Kao |
| collection | DOAJ |
| description | Dengue virus (DENV) infection can induce life-threatening dengue hemorrhagic fever/dengue shock syndrome in infected patients. DENV is a threat to global health due to its growing numbers and incidence of infection in the last 50 years. During infection, DENV expresses ten structural and nonstructural proteins modulating cell responses to benefit viral replication. However, the lack of knowledge regarding the cellular proteins and their functions in enhancing DENV pathogenesis impedes the development of antiviral drugs and therapies against fatal DENV infection. Here, we identified that integrin-linked kinase (ILK) is a novel enhancing factor for DENV infection by suppressing type I interferon (IFN) responses. Mechanistically, ILK binds DENV NS1 and NS3, activates Akt and Erk, and induces NF-κB-driven suppressor of cytokine signaling 3 (SOCS3) expression. Elevated SOCS3 in DENV-infected cells inhibits phosphorylation of STAT1/2 and expression of interferon-stimulated genes (ISGs). Inhibiting ILK, Akt, or Erk activation abrogates SOCS3 expression. In DENV-infected mice, the treatment of an ILK inhibitor significantly reduces viral loads in the brains, disease severity, and mortality rate. Collectively, our results show that ILK is a potential therapeutic target against DENV infection. |
| first_indexed | 2024-04-09T18:23:04Z |
| format | Article |
| id | doaj.art-424b8e3b23144c76b0b82920d9f58ff9 |
| institution | Directory Open Access Journal |
| issn | 1553-7366 1553-7374 |
| language | English |
| last_indexed | 2024-04-09T18:23:04Z |
| publishDate | 2023-03-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Pathogens |
| spelling | doaj.art-424b8e3b23144c76b0b82920d9f58ff92023-04-12T05:31:26ZengPublic Library of Science (PLoS)PLoS Pathogens1553-73661553-73742023-03-01193e101124110.1371/journal.ppat.1011241Negative regulation of type I interferon signaling by integrin-linked kinase permits dengue virus replication.Yi-Sheng KaoLi-Chiu WangPo-Chun ChangHeng-Ming LinYee-Shin LinChia-Yi YuChien-Chin ChenChiou-Feng LinTrai-Ming YehShu-Wen WanJen-Ren WangTzong-Shiann HoChien-Chou ChuBo-Cheng ZhangChih-Peng ChangDengue virus (DENV) infection can induce life-threatening dengue hemorrhagic fever/dengue shock syndrome in infected patients. DENV is a threat to global health due to its growing numbers and incidence of infection in the last 50 years. During infection, DENV expresses ten structural and nonstructural proteins modulating cell responses to benefit viral replication. However, the lack of knowledge regarding the cellular proteins and their functions in enhancing DENV pathogenesis impedes the development of antiviral drugs and therapies against fatal DENV infection. Here, we identified that integrin-linked kinase (ILK) is a novel enhancing factor for DENV infection by suppressing type I interferon (IFN) responses. Mechanistically, ILK binds DENV NS1 and NS3, activates Akt and Erk, and induces NF-κB-driven suppressor of cytokine signaling 3 (SOCS3) expression. Elevated SOCS3 in DENV-infected cells inhibits phosphorylation of STAT1/2 and expression of interferon-stimulated genes (ISGs). Inhibiting ILK, Akt, or Erk activation abrogates SOCS3 expression. In DENV-infected mice, the treatment of an ILK inhibitor significantly reduces viral loads in the brains, disease severity, and mortality rate. Collectively, our results show that ILK is a potential therapeutic target against DENV infection.https://doi.org/10.1371/journal.ppat.1011241 |
| spellingShingle | Yi-Sheng Kao Li-Chiu Wang Po-Chun Chang Heng-Ming Lin Yee-Shin Lin Chia-Yi Yu Chien-Chin Chen Chiou-Feng Lin Trai-Ming Yeh Shu-Wen Wan Jen-Ren Wang Tzong-Shiann Ho Chien-Chou Chu Bo-Cheng Zhang Chih-Peng Chang Negative regulation of type I interferon signaling by integrin-linked kinase permits dengue virus replication. PLoS Pathogens |
| title | Negative regulation of type I interferon signaling by integrin-linked kinase permits dengue virus replication. |
| title_full | Negative regulation of type I interferon signaling by integrin-linked kinase permits dengue virus replication. |
| title_fullStr | Negative regulation of type I interferon signaling by integrin-linked kinase permits dengue virus replication. |
| title_full_unstemmed | Negative regulation of type I interferon signaling by integrin-linked kinase permits dengue virus replication. |
| title_short | Negative regulation of type I interferon signaling by integrin-linked kinase permits dengue virus replication. |
| title_sort | negative regulation of type i interferon signaling by integrin linked kinase permits dengue virus replication |
| url | https://doi.org/10.1371/journal.ppat.1011241 |
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