【作者】 王舒宁；

【导师】 曹志伟；

【作者基本信息】 华东理工大学 ， 生物化工， 2012， 硕士

【摘要】 位于甲型流感病毒表面的HA蛋白的累积突变直接导致了流感病毒抗原性的改变,从而使其能够逃避宿主免疫系统的攻击。由于其持续的抗原性改变以及引发的多次大流行,人们越来越关注于是否可以提前预测到未来主要流行株的表位序列。因此,把握该病毒抗原性进化的轨迹并模拟其抗原性变化的过程是具有重大意义的。本课题根据19182008年间所收集到的1071条宿主为人的H1N1HA蛋白序列,依据宿主选择压力下抗原表位的突变特性构建了H1N1HA蛋白抗原表位预测模型。用1999-2008这10年的病毒序列数据对该模型的预测效果进行验证,结果表明,除极个别位点外,预测列表中前100位的表位序列可包含50%以上的真实病毒表位。接着对2009墨西哥流感随后可能出现的表位突变型做预测,发现除Sb位点外,2009/4/1-2010/9/30期间出现的其他四种真实表位,有50%以上包含在预测结果的前100个表位序列中。本法构建的H1N1HA抗原表位预测模型,也可进行跨流行周期的预测,从现有的流行株病毒抗原性较为准确的推测把握引发下一流行的病毒突变株。这可提高抗原漂变的监控水平,为大流感前的准备工作提供更多的信息。同时对于人群中传播的人感染的猪甲型H1N1流感病毒与人类季节性甲型H1N1流感病毒,分别收集了1918-2009年间17株人感染的猪甲型H1N1毒株以及21株季节性H1N1毒株,通过序列比对,氨基酸残基保守性分析以及3D结构对比等生物信息学方法来揭示造成这两者差异的原因。研究表明两者的抗原表位具有不同的进化速率。另外,受体结合位点的研究也显示这两类病毒RBS区域存在5个氨基酸水平的差异,分别为A138S,Q192K,S193T,Q196H以及A227E。这些研究结果为阐明两类甲型H1N1流感病毒性质差异提供了新的信息,并有助于进一步认识和理解流感病毒与宿主细胞作用及进化机制。更多还原

【Abstract】 Continual mutations on HA protein of influenza A virus generate novel antigenic strains that cause new outbreaks. Since the ongoing antigenic changes and annual epidemics it caused, more attention have been paid to whether the future dominant antigenic sequences for influenza virus A can be tracked and predicted or not. Consequently, describing and simulating the antigenic evolution of influenza A is of critical importance for reasonable preparation before a new pandemic. In this article, we have analyzed more than1071human A/H1N1HA sequences from1918to2008, and combined the evolutionary information and the mutation features in antigenic sites under host selection pressure to build a prediction model for H1N1HA antigenic variations. Then the accuracy of this prediction model was evaluated with sequences collected from1999——2011, the result shows that except for few sites, more than50%of the real epitope types can be covered by the top100of the prediction list both within an epidemic circulation and across circulations. This prediction model provides a convenient way to get future antigenic mutants with the genomic sequence of current prevalent strain, and can help the early prediction for antigenic drift in the forthcoming season. This may be of great significance for preventing and preparation before the new H1N1epidemic. In addition, in order to demonstrate the different infection characteristics of human infected swine H1N1and human seasonal H1N1,17HA(hemagglutinin) sequences of human infected swine H1N1and21human seasonal H1N1HA sequences have been collected, with bioinformatical method, including sequence alignment, amino acid conservational analysis and3D structure comparison to illustrate the mechanism for their diverse. The results revealed the conservational level on HA epitope sites is different for these two kinds H1N1viruses, and5amino acid differences on receptor binding sites have been found, including A138S,Q192K,S193T,Q196H and A227E. These results provide information for illustrating the diverse between these two kinds of H1N1, and can be helpful in understanding the evolution of human H1N1influenza viruses.更多还原