蝙蝠流感样病毒H17N10/H18N11血凝素蛋白结合唾液酸受体的潜力分析

Influenza is an acute, highly contagious disease caused by influenza viruses and often results in pandemics or epidemics among human beings and animals. Influenza pandemics and annual seasonal flu have led to great panics and economic losses. Shorebirds and waterfowls have been believed to be the reservoir hosts for influenza viruses until the recent identification of two influenza-like virus genomes (designated H17N10 and H18N11) from bats, which might indicate a more ancient origin. The bat-derived H17 and H18 do not bind to the sialic acids though they have the similar overall structures with that of the canonical HAs. This may due to amino acid substitutions in the putative receptor binding sites of H17 and H18. In this research we will analyze the potential binding of H17 and H18 to avian or human receptors by structure-guided site mutations combined with surface plasmon resonance (SPR) experiments, cell binding assays, glycan microarrays analysis as well as crystallography studies.

流感是由流感病毒引起的、流行于人群和多种动物中的急性、高度传染性疾病。大流感的暴发和季节性流感的传播严重威胁着人类健康并造成重大经济损失。流感病毒目前认为主要来源于野生水禽，但它的更早起源却不甚明了。最近，美国科学家们首次从蝙蝠里拿到了新的流感样病毒H17N10和H18N11的基因组信息，通过生物信息学分析，这类病毒可能是更为古老的流感病毒。紧接着的研究发现，H17/H18蛋白的整体结构与经典的HA蛋白类似，但受体结合位点氨基酸存在变异，导致不结合经典的唾液酸受体。本项目拟在结构分析的基础上，人工设计相应突变，通过生物物理技术，糖点阵检测技术，细胞学检测技术和蛋白晶体学技术等多种手段着重探索H17/H18蛋白的唾液酸受体结合潜力。本项目将系统地研究蝙蝠流感病毒的跨种传播潜力，为禽流感的防控提供理论和科学支撑。

本项目系统的评价了蝙蝠来源的流感病毒样血凝素蛋白H17受体结合域中经典的结合位点或其组合对人或禽唾液酸受体的亲和力的影响，为流感病毒的进化学说提出新的思路。在有2009甲型流感H1N1感染史的健康人群中成功筛选到能广泛中和两组亚型代表性流感病毒毒株（包括2013年我国多个地区暴发的H7N9亚型）的单克隆抗体CT149，并用结构生物学方法解析了CT149与H3及H7的复合物结构，阐明了该抗体结合血凝素蛋白的特殊结合模式，为寻找流感的通用治疗方法以及研制新型流感疫苗等提供了新线索（Nature Communications 2015）。此外，本项目开展了流感病毒神经氨酸酶药物研究，用结构生物学方法解释了2009H1N1甲型流感病毒株对第一组NA特异性抑制剂IG-173的药物敏感特性（Protein & Cell 2015）。