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Protection against dengue virus infection in mice by administration of antibodies against modified nonstructural protein 1.
PLoS One. 2014; 9(3):e92495.Plos

Abstract

BACKGROUND

Infection with dengue virus (DENV) may cause life-threatening disease with thrombocytopenia and vascular leakage which are related to dysfunction of platelets and endothelial cells. We previously showed that antibodies (Abs) against DENV nonstructural protein 1 (NS1) cross-react with human platelets and endothelial cells, leading to functional disturbances. Based on sequence homology analysis, the C-terminal region of DENV NS1 protein contains cross-reactive epitopes. For safety in vaccine development, the cross-reactive epitopes of DENV NS1 protein should be deleted or modified.

METHODOLOGY/PRINCIPAL FINDINGS

We tested the protective effects of Abs against full-length DENV NS1, NS1 lacking the C-terminal amino acids (a.a.) 271-352 (designated ΔC NS1), and chimeric DJ NS1 consisting of N-terminal DENV NS1 (a.a. 1-270) and C-terminal Japanese encephalitis virus NS1 (a.a. 271-352). The anti-ΔC NS1 and anti-DJ NS1 Abs showed a lower binding activity to endothelial cells and platelets than that of anti-DENV NS1 Abs. Passive immunization with anti-ΔC NS1 and anti-DJ NS1 Abs reduced DENV-induced prolonged mouse tail bleeding time. Treatment with anti-DENV NS1, anti-ΔC NS1 and anti-DJ NS1 Abs reduced local skin hemorrhage, controlled the viral load of DENV infection in vivo, synergized with complement to inhibit viral replication in vitro, as well as abolished DENV-induced macrophage infiltration to the site of skin inoculation. Moreover, active immunization with modified NS1 protein, but not with unmodified DENV NS1 protein, reduced DENV-induced prolonged bleeding time, local skin hemorrhage, and viral load.

CONCLUSIONS/SIGNIFICANCE

These results support the idea that modified NS1 proteins may represent an improved strategy for safe and effective vaccine development against DENV infection.

Authors+Show Affiliations

Center of Infectious Disease and Signaling Research, National Cheng Kung University, Tainan, Taiwan; Department of Microbiology and Immunology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.Department of Microbiology and Immunology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.Department of Microbiology and Immunology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.Center of Infectious Disease and Signaling Research, National Cheng Kung University, Tainan, Taiwan; Department of Microbiology and Immunology, College of Medicine, National Cheng Kung University, Tainan, Taiwan; Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan.Department of Microbiology and Immunology, Dalhousie University, Halifax, Nova Scotia, Canada.Center of Infectious Disease and Signaling Research, National Cheng Kung University, Tainan, Taiwan; Department of Microbiology and Immunology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.Center of Infectious Disease and Signaling Research, National Cheng Kung University, Tainan, Taiwan; Department of Medical Laboratory Science and Biotechnology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.Graduate Institute of Immunology, College of Medicine, National Taiwan University, Taipei, Taiwan.Graduate Institute of Immunology, College of Medicine, National Taiwan University, Taipei, Taiwan.Center of Infectious Disease and Signaling Research, National Cheng Kung University, Tainan, Taiwan; Department of Microbiology and Immunology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.

Pub Type(s)

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

Language

eng

PubMed ID

24658118

Citation

Wan, Shu-Wen, et al. "Protection Against Dengue Virus Infection in Mice By Administration of Antibodies Against Modified Nonstructural Protein 1." PloS One, vol. 9, no. 3, 2014, pp. e92495.
Wan SW, Lu YT, Huang CH, et al. Protection against dengue virus infection in mice by administration of antibodies against modified nonstructural protein 1. PLoS One. 2014;9(3):e92495.
Wan, S. W., Lu, Y. T., Huang, C. H., Lin, C. F., Anderson, R., Liu, H. S., Yeh, T. M., Yen, Y. T., Wu-Hsieh, B. A., & Lin, Y. S. (2014). Protection against dengue virus infection in mice by administration of antibodies against modified nonstructural protein 1. PloS One, 9(3), e92495. https://doi.org/10.1371/journal.pone.0092495
Wan SW, et al. Protection Against Dengue Virus Infection in Mice By Administration of Antibodies Against Modified Nonstructural Protein 1. PLoS One. 2014;9(3):e92495. PubMed PMID: 24658118.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Protection against dengue virus infection in mice by administration of antibodies against modified nonstructural protein 1. AU - Wan,Shu-Wen, AU - Lu,Yi-Tien, AU - Huang,Chia-Hui, AU - Lin,Chiou-Feng, AU - Anderson,Robert, AU - Liu,Hsiao-Sheng, AU - Yeh,Trai-Ming, AU - Yen,Yu-Ting, AU - Wu-Hsieh,Betty A, AU - Lin,Yee-Shin, Y1 - 2014/03/21/ PY - 2013/12/17/received PY - 2014/02/21/accepted PY - 2014/3/25/entrez PY - 2014/3/25/pubmed PY - 2015/1/21/medline SP - e92495 EP - e92495 JF - PloS one JO - PLoS One VL - 9 IS - 3 N2 - BACKGROUND: Infection with dengue virus (DENV) may cause life-threatening disease with thrombocytopenia and vascular leakage which are related to dysfunction of platelets and endothelial cells. We previously showed that antibodies (Abs) against DENV nonstructural protein 1 (NS1) cross-react with human platelets and endothelial cells, leading to functional disturbances. Based on sequence homology analysis, the C-terminal region of DENV NS1 protein contains cross-reactive epitopes. For safety in vaccine development, the cross-reactive epitopes of DENV NS1 protein should be deleted or modified. METHODOLOGY/PRINCIPAL FINDINGS: We tested the protective effects of Abs against full-length DENV NS1, NS1 lacking the C-terminal amino acids (a.a.) 271-352 (designated ΔC NS1), and chimeric DJ NS1 consisting of N-terminal DENV NS1 (a.a. 1-270) and C-terminal Japanese encephalitis virus NS1 (a.a. 271-352). The anti-ΔC NS1 and anti-DJ NS1 Abs showed a lower binding activity to endothelial cells and platelets than that of anti-DENV NS1 Abs. Passive immunization with anti-ΔC NS1 and anti-DJ NS1 Abs reduced DENV-induced prolonged mouse tail bleeding time. Treatment with anti-DENV NS1, anti-ΔC NS1 and anti-DJ NS1 Abs reduced local skin hemorrhage, controlled the viral load of DENV infection in vivo, synergized with complement to inhibit viral replication in vitro, as well as abolished DENV-induced macrophage infiltration to the site of skin inoculation. Moreover, active immunization with modified NS1 protein, but not with unmodified DENV NS1 protein, reduced DENV-induced prolonged bleeding time, local skin hemorrhage, and viral load. CONCLUSIONS/SIGNIFICANCE: These results support the idea that modified NS1 proteins may represent an improved strategy for safe and effective vaccine development against DENV infection. SN - 1932-6203 UR - https://www.unboundmedicine.com/medline/citation/24658118/Protection_against_dengue_virus_infection_in_mice_by_administration_of_antibodies_against_modified_nonstructural_protein_1_ L2 - https://dx.plos.org/10.1371/journal.pone.0092495 DB - PRIME DP - Unbound Medicine ER -