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Therapeutic Effects of Monoclonal Antibody against Dengue Virus NS1 in a STAT1 Knockout Mouse Model of Dengue Infection.
J Immunol. 2017 10 15; 199(8):2834-2844.JI

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.

Authors+Show Affiliations

Center of Infectious Disease and Signaling Research, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan. Department of Microbiology and Immunology, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan. School of Medicine, College of Medicine, I-Shou University, Kaohsiung 824, Taiwan.Department of Microbiology and Immunology, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan.Department of Microbiology and Immunology, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan.Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan. Department of Medical Laboratory Science and Biotechnology, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan.Department of Microbiology and Immunology, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan.Department of Microbiology and Immunology, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan.Department of Microbiology and Immunology, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan.Department of Medicine, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan.Department of Medical Laboratory Science and Biotechnology, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan.Department of Medical Laboratory Science and Biotechnology, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan.Center of Infectious Disease and Signaling Research, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan. Department of Microbiology and Immunology, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan.Center of Infectious Disease and Signaling Research, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan. Department of Microbiology and Immunology, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan.Center of Infectious Disease and Signaling Research, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan. Department of Pediatrics, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan.Center of Infectious Disease and Signaling Research, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan. Department of Pediatrics, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan.Center of Infectious Disease and Signaling Research, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan. Department of Microbiology and Immunology, College of Medicine, Taipei Medical University, Taipei 110, Taiwan.Graduate Institute of Immunology, National Taiwan University College of Medicine, Taipei 100, Taiwan.Graduate Institute of Immunology, National Taiwan University College of Medicine, Taipei 100, Taiwan.Department of Microbiology and Immunology, Dalhousie University, Halifax, Nova Scotia B3H 4R2, Canada. Department of Pediatrics, Dalhousie University, Halifax, Nova Scotia B3H 4R2, Canada; and. Canadian Center for Vaccinology, Dalhousie University, Halifax, Nova Scotia B3H 4R2, Canada.Center of Infectious Disease and Signaling Research, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan; today@mail.ncku.edu.tw yslin1@mail.ncku.edu.tw. Department of Medical Laboratory Science and Biotechnology, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan.Center of Infectious Disease and Signaling Research, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan; today@mail.ncku.edu.tw yslin1@mail.ncku.edu.tw. Department of Microbiology and Immunology, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

28904127

Citation

Wan, Shu-Wen, et al. "Therapeutic Effects of Monoclonal Antibody Against Dengue Virus NS1 in a STAT1 Knockout Mouse Model of Dengue Infection." Journal of Immunology (Baltimore, Md. : 1950), vol. 199, no. 8, 2017, pp. 2834-2844.
Wan SW, Chen PW, Chen CY, et al. Therapeutic Effects of Monoclonal Antibody against Dengue Virus NS1 in a STAT1 Knockout Mouse Model of Dengue Infection. J Immunol. 2017;199(8):2834-2844.
Wan, S. W., Chen, P. W., Chen, C. Y., Lai, Y. C., Chu, Y. T., Hung, C. Y., Lee, H., Wu, H. F., Chuang, Y. C., Lin, J., Chang, C. P., Wang, S., Liu, C. C., Ho, T. S., Lin, C. F., Lee, C. K., Wu-Hsieh, B. A., 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 (Baltimore, Md. : 1950), 199(8), 2834-2844. https://doi.org/10.4049/jimmunol.1601523
Wan SW, et al. Therapeutic Effects of Monoclonal Antibody Against Dengue Virus NS1 in a STAT1 Knockout Mouse Model of Dengue Infection. J Immunol. 2017 10 15;199(8):2834-2844. PubMed PMID: 28904127.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Therapeutic Effects of Monoclonal Antibody against Dengue Virus NS1 in a STAT1 Knockout Mouse Model of Dengue Infection. AU - Wan,Shu-Wen, 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,Shuying, 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, Y1 - 2017/09/13/ PY - 2016/08/31/received PY - 2017/08/14/accepted PY - 2017/9/15/pubmed PY - 2017/11/2/medline PY - 2017/9/15/entrez SP - 2834 EP - 2844 JF - Journal of immunology (Baltimore, Md. : 1950) JO - J Immunol VL - 199 IS - 8 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. SN - 1550-6606 UR - https://www.unboundmedicine.com/medline/citation/28904127/Therapeutic_Effects_of_Monoclonal_Antibody_against_Dengue_Virus_NS1_in_a_STAT1_Knockout_Mouse_Model_of_Dengue_Infection_ L2 - http://www.jimmunol.org/cgi/pmidlookup?view=long&pmid=28904127 DB - PRIME DP - Unbound Medicine ER -