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, Shuying 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

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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.

Original languageEnglish
Pages (from-to)2834-2844
Number of pages11
JournalJournal of Immunology
Volume199
Issue number8
DOIs
Publication statusPublished - Oct 15 2017

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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

ASJC Scopus subject areas

  • Immunology

Cite this

Wan, S. W., Chen, P. W., Chen, C. Y., Lai, Y. C., Chu, Y. T., Hung, C. Y., ... 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, 199(8), 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, Shuying; Liu, Ching Chuan; Ho, Tzong Shiann; Lin, Chiou Feng; Lee, Chien Kuo; Wu-Hsieh, Betty A.; Anderson, Robert; Yeh, Trai Ming; Lin, Yee Shin.

In: Journal of Immunology, Vol. 199, No. 8, 15.10.2017, p. 2834-2844.

Research output: Contribution to journalArticle

Wan, SW, Chen, PW, Chen, CY, Lai, YC, Chu, YT, Hung, CY, Lee, H, Wu, HF, Chuang, YC, Lin, J, Chang, CP, Wang, S, Liu, CC, Ho, TS, Lin, CF, Lee, CK, Wu-Hsieh, BA, Anderson, R, Yeh, TM & Lin, YS 2017, 'Therapeutic effects of monoclonal antibody against dengue virus NS1 in a STAT1 knockout mouse model of dengue infection', Journal of Immunology, vol. 199, no. 8, pp. 2834-2844. https://doi.org/10.4049/jimmunol.1601523
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, Shuying ; 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. In: Journal of Immunology. 2017 ; Vol. 199, No. 8. pp. 2834-2844.
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AU - Hung, Chia Yi

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AU - Wu, Hsuan Franziska

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AU - Lin, Jessica

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AU - Liu, Ching Chuan

AU - Ho, Tzong Shiann

AU - Lin, Chiou Feng

AU - Lee, Chien Kuo

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AU - Yeh, Trai Ming

AU - Lin, Yee Shin

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