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利用一种与登革热发生交叉反应的单克隆抗体鉴定登革热前膜蛋白上的一个新的感染增强表位。

Identification of a novel infection-enhancing epitope on dengue prM using a dengue cross-reacting monoclonal antibody.

机构信息

Key Laboratory for Tropic Diseases Control, Ministry of Education of China, Department of Microbiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China.

出版信息

BMC Microbiol. 2013 Aug 29;13:194. doi: 10.1186/1471-2180-13-194.

DOI:10.1186/1471-2180-13-194
PMID:23987307
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC3765915/
Abstract

BACKGROUND

Dengue virus (DENV) infection is the most important arthropod- borne viral disease in human, but antiviral therapy and approved vaccines remain unavailable due to antibody-dependent enhancement (ADE) phenomenon. Many studies showed that pre-membrane (prM)-specific antibodies do not efficiently neutralize DENV infection but potently promote ADE infection. However, most of the binding epitopes of these antibodies remain unknown.

RESULTS

In the present study, we characterized a DENV cross-reactive monoclonal antibody (mAb), 4D10, that neutralized poorly but potently enhanced infection of four standard DENV serotypes and immature DENV (imDENV) over a broad range of concentration. In addition, the epitope of 4D10 was successfully mapped to amino acid residues 14 to18 of DENV1-4 prM protein using a phage-displayed peptide library and comprehensive bioinformatics analysis. We found that the epitope was DENV serocomplex cross-reactive and showed to be highly immunogenic in Balb/c mice. Furthermore, antibody against epitope peptide PL10, like 4D10, showed broad cross-reactivity and weak neutralizing activtity with four standard DENV serotypes and imDENV but significantly promoted ADE infection. These results suggested 4D10 and anti-PL10 sera were infection-enhancing antibodies and PL10 was infection-enhancing epitope.

CONCLUSIONS

We mapped the epitope of 4D10 to amino acid residues 14 to18 of DENV1-4 prM and found that this epitope was infection-enhancing. These findings may provide significant implications for future vaccine design and facilitate understanding the pathogenesis of DENV infection.

摘要

背景

登革热病毒（DENV）感染是人类最重要的虫媒病毒病，但由于抗体依赖性增强（ADE）现象，抗病毒治疗和批准的疫苗仍然不可用。许多研究表明，膜前（prM）特异性抗体不能有效地中和 DENV 感染，但能强烈促进 ADE 感染。然而，这些抗体的大多数结合表位仍然未知。

结果

在本研究中，我们鉴定了一种 DENV 交叉反应性单克隆抗体（mAb）4D10，该抗体对四种标准 DENV 血清型和未成熟 DENV（imDENV）的中和作用很差，但在广泛的浓度范围内强烈增强感染。此外，使用噬菌体展示肽文库和综合生物信息学分析，成功地将 4D10 的表位映射到 DENV1-4 prM 蛋白的 14 至 18 位氨基酸。我们发现该表位是 DENV 血清型交叉反应性的，并且在 Balb/c 小鼠中表现出高度的免疫原性。此外，针对表位肽 PL10 的抗体与 4D10 一样，对四种标准 DENV 血清型和 imDENV 具有广泛的交叉反应性和较弱的中和活性，但能显著促进 ADE 感染。这些结果表明 4D10 和抗-PL10 血清是感染增强抗体，PL10 是感染增强表位。

结论

我们将 4D10 的表位映射到 DENV1-4 prM 的 14 至 18 位氨基酸，发现该表位是感染增强性的。这些发现可能为未来的疫苗设计提供重要意义，并有助于理解 DENV 感染的发病机制。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cf83/3765915/54b212dfdfa4/1471-2180-13-194-8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cf83/3765915/abb82a98d5d7/1471-2180-13-194-1.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cf83/3765915/d78c0709aa5b/1471-2180-13-194-4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cf83/3765915/20208af90f96/1471-2180-13-194-5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cf83/3765915/e48d2e8cf4e0/1471-2180-13-194-6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cf83/3765915/d11e4bbafed6/1471-2180-13-194-7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cf83/3765915/54b212dfdfa4/1471-2180-13-194-8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cf83/3765915/abb82a98d5d7/1471-2180-13-194-1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cf83/3765915/51d41db1f259/1471-2180-13-194-2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cf83/3765915/0e2e9c25ba89/1471-2180-13-194-3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cf83/3765915/d78c0709aa5b/1471-2180-13-194-4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cf83/3765915/20208af90f96/1471-2180-13-194-5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cf83/3765915/e48d2e8cf4e0/1471-2180-13-194-6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cf83/3765915/d11e4bbafed6/1471-2180-13-194-7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cf83/3765915/54b212dfdfa4/1471-2180-13-194-8.jpg

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