Protection against dengue virus infection in mice by administration of antibodies against modified nonstructural protein 1

Shu Wen Wan, Yi Tien Lu, Chia Hui Huang, Chiou Feng Lin, Robert Anderson, Hsiao-Sheng Liu, Trai-Ming Yeh, Yu Ting Yen, Betty A. Wu-Hsieh, Yee-Shin Lin

Research output: Contribution to journalArticle

24 Citations (Scopus)

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 DC 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.

Original languageEnglish
Article numbere92495
JournalPloS one
Volume9
Issue number3
DOIs
Publication statusPublished - 2014 Mar 21

Fingerprint

Dengue virus
Dengue Virus
Virus Diseases
Viruses
antibodies
Antibodies
mice
infection
Proteins
proteins
Protein C
hemorrhage
Bleeding Time
Endothelial cells
Blood Platelets
Endothelial Cells
Platelets
skin (animal)
Viral Load
endothelial cells

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Wan, Shu Wen ; Lu, Yi Tien ; Huang, Chia Hui ; Lin, Chiou Feng ; Anderson, Robert ; Liu, Hsiao-Sheng ; Yeh, Trai-Ming ; Yen, Yu Ting ; Wu-Hsieh, Betty A. ; Lin, Yee-Shin. / Protection against dengue virus infection in mice by administration of antibodies against modified nonstructural protein 1. In: PloS one. 2014 ; Vol. 9, No. 3.
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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 DC 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.",
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Protection against dengue virus infection in mice by administration of antibodies against modified nonstructural protein 1. / Wan, Shu Wen; Lu, Yi Tien; Huang, Chia Hui; Lin, Chiou Feng; Anderson, Robert; Liu, Hsiao-Sheng; Yeh, Trai-Ming; Yen, Yu Ting; Wu-Hsieh, Betty A.; Lin, Yee-Shin.

In: PloS one, Vol. 9, No. 3, e92495, 21.03.2014.

Research output: Contribution to journalArticle

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AU - Wan, Shu Wen

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AU - Huang, Chia Hui

AU - Lin, Chiou Feng

AU - Anderson, Robert

AU - Liu, Hsiao-Sheng

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AB - 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 DC 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.

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