Therapeutic effects of monoclonal antibody against dengue virus NS1 in a STAT1 knockout mouse model of dengue infection

Shu Wen Wan, Pei Wei Chen, Chin Yu Chen, Yen Chung Lai, Ya Ting Chu, Chia Yi Hung, Han Lee, Hsuan Franziska Wu, Yung Chun Chuang, Jessica Lin, Chih-Peng Chang, Shu-Ying Wang, Ching-Chuan Liu, Tzong-Shiann Ho, Chiou Feng Lin, Chien Kuo Lee, Betty A. Wu-Hsieh, Robert Anderson, Trai-Ming Yeh, Yee-Shin Lin

研究成果: Article

10 引文 (Scopus)

摘要

Dengue virus (DENV) is the causative agent of dengue fever, dengue hemorrhagic fever, and dengue shock syndrome and is endemic to tropical and subtropical regions of the world. Our previous studies showed the existence of epitopes in the C-terminal region of DENV nonstructural protein 1 (NS1) which are cross-reactive with host Ags and trigger anti-DENV NS1 Ab-mediated endothelial cell damage and platelet dysfunction. To circumvent these potentially harmful events, we replaced the C-terminal region of DENV NS1 with the corresponding region from Japanese encephalitis virus NS1 to create chimeric DJ NS1 protein. Passive immunization of DENV-infected mice with polyclonal anti-DJ NS1 Abs reduced viral Ag expression at skin inoculation sites and shortened DENV-induced prolonged bleeding time. We also investigated the therapeutic effects of anti-NS1 mAb. One mAb designated 2E8 does not recognize the C-terminal region of DENV NS1 in which host-cross-reactive epitopes reside. Moreover, mAb 2E8 recognizes NS1 of all four DENV serotypes. We also found that mAb 2E8 caused complement-mediated lysis in DENV-infected cells. In mouse model studies, treatment with mAb 2E8 shortened DENV-induced prolonged bleeding time and reduced viral Ag expression in the skin. Importantly, mAb 2E8 provided therapeutic effects against all four serotypes of DENV. We further found that mAb administration to mice as late as 1 d prior to severe bleeding still reduced prolonged bleeding time and hemorrhage. Therefore, administration with a single dose of mAb 2E8 can protect mice against DENV infection and pathological effects, suggesting that NS1-specific mAb may be a therapeutic option against dengue disease.

原文English
頁(從 - 到)2834-2844
頁數11
期刊Journal of Immunology
199
發行號8
DOIs
出版狀態Published - 2017 十月 15

指紋

Dengue Virus
Dengue
Therapeutic Uses
Knockout Mice
Monoclonal Antibodies
Infection
Proteins
Severe Dengue
Bleeding Time
Japanese Encephalitis Virus
Epitopes
Hemorrhage
Skin
Passive Immunization
Virus Diseases
Blood Platelets
Endothelial Cells

All Science Journal Classification (ASJC) codes

  • Immunology

引用此文

Wan, Shu Wen ; Chen, Pei Wei ; Chen, Chin Yu ; Lai, Yen Chung ; Chu, Ya Ting ; Hung, Chia Yi ; Lee, Han ; Wu, Hsuan Franziska ; Chuang, Yung Chun ; Lin, Jessica ; Chang, Chih-Peng ; Wang, Shu-Ying ; Liu, Ching-Chuan ; Ho, Tzong-Shiann ; Lin, Chiou Feng ; Lee, Chien Kuo ; Wu-Hsieh, Betty A. ; Anderson, Robert ; Yeh, Trai-Ming ; Lin, Yee-Shin. / Therapeutic effects of monoclonal antibody against dengue virus NS1 in a STAT1 knockout mouse model of dengue infection. 於: Journal of Immunology. 2017 ; 卷 199, 編號 8. 頁 2834-2844.
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title = "Therapeutic effects of monoclonal antibody against dengue virus NS1 in a STAT1 knockout mouse model of dengue infection",
abstract = "Dengue virus (DENV) is the causative agent of dengue fever, dengue hemorrhagic fever, and dengue shock syndrome and is endemic to tropical and subtropical regions of the world. Our previous studies showed the existence of epitopes in the C-terminal region of DENV nonstructural protein 1 (NS1) which are cross-reactive with host Ags and trigger anti-DENV NS1 Ab-mediated endothelial cell damage and platelet dysfunction. To circumvent these potentially harmful events, we replaced the C-terminal region of DENV NS1 with the corresponding region from Japanese encephalitis virus NS1 to create chimeric DJ NS1 protein. Passive immunization of DENV-infected mice with polyclonal anti-DJ NS1 Abs reduced viral Ag expression at skin inoculation sites and shortened DENV-induced prolonged bleeding time. We also investigated the therapeutic effects of anti-NS1 mAb. One mAb designated 2E8 does not recognize the C-terminal region of DENV NS1 in which host-cross-reactive epitopes reside. Moreover, mAb 2E8 recognizes NS1 of all four DENV serotypes. We also found that mAb 2E8 caused complement-mediated lysis in DENV-infected cells. In mouse model studies, treatment with mAb 2E8 shortened DENV-induced prolonged bleeding time and reduced viral Ag expression in the skin. Importantly, mAb 2E8 provided therapeutic effects against all four serotypes of DENV. We further found that mAb administration to mice as late as 1 d prior to severe bleeding still reduced prolonged bleeding time and hemorrhage. Therefore, administration with a single dose of mAb 2E8 can protect mice against DENV infection and pathological effects, suggesting that NS1-specific mAb may be a therapeutic option against dengue disease.",
author = "Wan, {Shu Wen} and Chen, {Pei Wei} and Chen, {Chin Yu} and Lai, {Yen Chung} and Chu, {Ya Ting} and Hung, {Chia Yi} and Han Lee and Wu, {Hsuan Franziska} and Chuang, {Yung Chun} and Jessica Lin and Chih-Peng Chang and Shu-Ying Wang and Ching-Chuan Liu and Tzong-Shiann Ho and Lin, {Chiou Feng} and Lee, {Chien Kuo} and Wu-Hsieh, {Betty A.} and Robert Anderson and Trai-Ming Yeh and Yee-Shin Lin",
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Wan, SW, Chen, PW, Chen, CY, Lai, YC, Chu, YT, Hung, CY, Lee, H, Wu, HF, Chuang, YC, Lin, J, Chang, C-P, Wang, S-Y, Liu, C-C, Ho, T-S, Lin, CF, Lee, CK, Wu-Hsieh, BA, Anderson, R, Yeh, T-M & Lin, Y-S 2017, 'Therapeutic effects of monoclonal antibody against dengue virus NS1 in a STAT1 knockout mouse model of dengue infection', Journal of Immunology, 卷 199, 編號 8, 頁 2834-2844. https://doi.org/10.4049/jimmunol.1601523

Therapeutic effects of monoclonal antibody against dengue virus NS1 in a STAT1 knockout mouse model of dengue infection. / Wan, Shu Wen; Chen, Pei Wei; Chen, Chin Yu; Lai, Yen Chung; Chu, Ya Ting; Hung, Chia Yi; Lee, Han; Wu, Hsuan Franziska; Chuang, Yung Chun; Lin, Jessica; Chang, Chih-Peng; Wang, Shu-Ying; Liu, Ching-Chuan; Ho, Tzong-Shiann; Lin, Chiou Feng; Lee, Chien Kuo; Wu-Hsieh, Betty A.; Anderson, Robert; Yeh, Trai-Ming; Lin, Yee-Shin.

於: Journal of Immunology, 卷 199, 編號 8, 15.10.2017, p. 2834-2844.

研究成果: Article

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T1 - Therapeutic effects of monoclonal antibody against dengue virus NS1 in a STAT1 knockout mouse model of dengue infection

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AU - Chen, Pei Wei

AU - Chen, Chin Yu

AU - Lai, Yen Chung

AU - Chu, Ya Ting

AU - Hung, Chia Yi

AU - Lee, Han

AU - Wu, Hsuan Franziska

AU - Chuang, Yung Chun

AU - Lin, Jessica

AU - Chang, Chih-Peng

AU - Wang, Shu-Ying

AU - Liu, Ching-Chuan

AU - Ho, Tzong-Shiann

AU - Lin, Chiou Feng

AU - Lee, Chien Kuo

AU - Wu-Hsieh, Betty A.

AU - Anderson, Robert

AU - Yeh, Trai-Ming

AU - Lin, Yee-Shin

PY - 2017/10/15

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N2 - Dengue virus (DENV) is the causative agent of dengue fever, dengue hemorrhagic fever, and dengue shock syndrome and is endemic to tropical and subtropical regions of the world. Our previous studies showed the existence of epitopes in the C-terminal region of DENV nonstructural protein 1 (NS1) which are cross-reactive with host Ags and trigger anti-DENV NS1 Ab-mediated endothelial cell damage and platelet dysfunction. To circumvent these potentially harmful events, we replaced the C-terminal region of DENV NS1 with the corresponding region from Japanese encephalitis virus NS1 to create chimeric DJ NS1 protein. Passive immunization of DENV-infected mice with polyclonal anti-DJ NS1 Abs reduced viral Ag expression at skin inoculation sites and shortened DENV-induced prolonged bleeding time. We also investigated the therapeutic effects of anti-NS1 mAb. One mAb designated 2E8 does not recognize the C-terminal region of DENV NS1 in which host-cross-reactive epitopes reside. Moreover, mAb 2E8 recognizes NS1 of all four DENV serotypes. We also found that mAb 2E8 caused complement-mediated lysis in DENV-infected cells. In mouse model studies, treatment with mAb 2E8 shortened DENV-induced prolonged bleeding time and reduced viral Ag expression in the skin. Importantly, mAb 2E8 provided therapeutic effects against all four serotypes of DENV. We further found that mAb administration to mice as late as 1 d prior to severe bleeding still reduced prolonged bleeding time and hemorrhage. Therefore, administration with a single dose of mAb 2E8 can protect mice against DENV infection and pathological effects, suggesting that NS1-specific mAb may be a therapeutic option against dengue disease.

AB - Dengue virus (DENV) is the causative agent of dengue fever, dengue hemorrhagic fever, and dengue shock syndrome and is endemic to tropical and subtropical regions of the world. Our previous studies showed the existence of epitopes in the C-terminal region of DENV nonstructural protein 1 (NS1) which are cross-reactive with host Ags and trigger anti-DENV NS1 Ab-mediated endothelial cell damage and platelet dysfunction. To circumvent these potentially harmful events, we replaced the C-terminal region of DENV NS1 with the corresponding region from Japanese encephalitis virus NS1 to create chimeric DJ NS1 protein. Passive immunization of DENV-infected mice with polyclonal anti-DJ NS1 Abs reduced viral Ag expression at skin inoculation sites and shortened DENV-induced prolonged bleeding time. We also investigated the therapeutic effects of anti-NS1 mAb. One mAb designated 2E8 does not recognize the C-terminal region of DENV NS1 in which host-cross-reactive epitopes reside. Moreover, mAb 2E8 recognizes NS1 of all four DENV serotypes. We also found that mAb 2E8 caused complement-mediated lysis in DENV-infected cells. In mouse model studies, treatment with mAb 2E8 shortened DENV-induced prolonged bleeding time and reduced viral Ag expression in the skin. Importantly, mAb 2E8 provided therapeutic effects against all four serotypes of DENV. We further found that mAb administration to mice as late as 1 d prior to severe bleeding still reduced prolonged bleeding time and hemorrhage. Therefore, administration with a single dose of mAb 2E8 can protect mice against DENV infection and pathological effects, suggesting that NS1-specific mAb may be a therapeutic option against dengue disease.

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