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

研究成果: 雜誌貢獻文章同行評審

48 引文 斯高帕斯(Scopus)

摘要

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.

原文英語
文章編號e92495
期刊PLoS One
9
發行號3
DOIs
出版狀態已發佈 - 3月 21 2014
對外發佈

ASJC Scopus subject areas

  • 農業與生物科學 (全部)
  • 生物化學、遺傳與分子生物學 (全部)
  • 醫藥 (全部)

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