Large-scale analysis of B-cell epitopes on influenza virus hemagglutinin - implications for cross-reactivity of neutralizing antibodies.
Large-scale analysis of B-cell epitopes on influenza virus hemagglutinin - implications for cross-reactivity of neutralizing antibodies.
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DOI：
10.3389/fimmu.2014.00038
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发表时间：
2014
影响因子：
7.3
通讯作者：
Brusic V
中科院分区：
文献类型：
--
作者：
Sun J;Kudahl UJ;Simon C;Cao Z;Reinherz EL;Brusic V
流感病毒继续在世界范围内造成相当大的发病率和死亡率。流感病毒表面蛋白的快速基因突变导致对现有疫苗和现有抗病毒药物的耐药性增加。广谱中和抗体(BNAbs)是流感预防和治疗的靶点。我们对中和抗体(NAB)与流感病毒表面糖蛋白血凝素(HA)的交叉反应进行了系统的生物信息学研究。本研究利用已有的HA与抗体结合的晶体结构对数万个HA序列进行了分析。对B细胞表位的详细描述，不同毒株之间表位区域相似性的测量，以及抗体中和覆盖率的估计，为了解现有NAB对流感病毒的交叉反应状态提供了深入的了解。我们已经开发了一种方法来评估bNAbs对新出现的或现有的流感毒株可能的交叉反应潜力。我们的方法通过一个名为不连续肽的新概念对流感病毒株进行分类，然后提供交叉反应的评估。潜在的交叉反应菌株是那些与实验验证的中和菌株100%相同的菌株。通过编目已知bNAbs的流感毒株及其B细胞表位，我们的方法为进一步的实验设计选择具有代表性的毒株提供了指导。通过对序列、其B细胞表位以及历史流感毒株之间的差异的了解，我们加强了对新出现的大流行威胁的准备和应对能力。
Influenza viruses continue to cause substantial morbidity and mortality worldwide. Fast gene mutation on surface proteins of influenza virus result in increasing resistance to current vaccines and available antiviral drugs. Broadly neutralizing antibodies (bnAbs) represent targets for prophylactic and therapeutic treatments of influenza. We performed a systematic bioinformatics study of cross-reactivity of neutralizing antibodies (nAbs) against influenza virus surface glycoprotein hemagglutinin (HA). This study utilized the available crystal structures of HA complexed with the antibodies for the analysis of tens of thousands of HA sequences. The detailed description of B-cell epitopes, measurement of epitope area similarity among different strains, and estimation of antibody neutralizing coverage provide insights into cross-reactivity status of existing nAbs against influenza virus. We have developed a method to assess the likely cross-reactivity potential of bnAbs for influenza strains, either newly emerged or existing. Our method catalogs influenza strains by a new concept named discontinuous peptide, and then provide assessment of cross-reactivity. Potentially cross-reactive strains are those that share 100% identity with experimentally verified neutralized strains. By cataloging influenza strains and their B-cell epitopes for known bnAbs, our method provides guidance for selection of representative strains for further experimental design. The knowledge of sequences, their B-cell epitopes, and differences between historical influenza strains, we enhance our preparedness and the ability to respond to the emerging pandemic threats.
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