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人B组腺病毒纤毛蛋白与DSG2受体亲和力的差异及其对病毒致病力的影响研究

批准号31570163 学科分类病毒增殖与演化 ( C010803 )
项目负责人田新贵 负责人职称主管技师 依托单位广州医科大学
资助金额62.00
万元
项目类别面上项目 研究期限2016 年 01 月 01 日 至
2019 年 12 月 31 日
中文主题词腺病毒;纤毛蛋白;病毒结构;病毒受体;致病力
英文主题词adenovirus;fibre;virion structure;virus receptor;virulent

摘要

中文摘要 在致急性呼吸道感染的腺病毒中,人B组3型最常见,而7、55、14型常引起重症感染。不同于其它型别腺病毒识别CAR或CD46等受体,这几种腺病毒均以纤毛蛋白结合受体桥粒芯蛋白2(DSG2)。我们发现人7、14、55型腺病毒纤毛蛋白高度同源,而与3型纤毛蛋白同源性较低;人7、55、14型腺病毒的感染能力较3型更强。人7、55、14型腺病毒的高致病力是否和纤毛蛋白有关?影响纤毛蛋白与DSG2结合的关键性氨基酸?我们已经制备了重组人3、7、55型腺病毒,本课题将表达野生型、突变型纤毛蛋白,构建纤毛蛋白置换及突变的的嵌合腺病毒等,比较人3、7、55型腺病毒纤毛蛋白与DSG2亲和力,鉴定与DSG2结合的关键性氨基酸,并利用紧密连接细胞模型和我们建立的树鼩感染模型,探讨纤毛蛋白对腺病毒致病和重症化的作用与机制,为高致病腺病毒预警、开发新型腺病毒载体、疫苗和药物提供理论基础。
英文摘要 Human adenovirus type 3 (HAdV-B3) of B species is the most common type, however, Human adenovirus type 7 (HAdV-B7) and 14 (HAdV-B14), 55 (HAdV-B55) have more virulent, and tend to cause severe pneumonia even death among the adenoviruses causing acute respiratory infection. Recently it has been proved that all the four types detect Desmoglein 2 (DSG2) as receptor, not CAR or CD46 detected by other human adenovirus types. The amino acid similarities between fibres of HAdV-B7 and B14, B55 are up to 92%, but only 57-58% between HAdV-B7 and B3. We also found that HAdV-B7 and B14, B55 have higher infectivities to cells than HAdV-B3. Then there are two quenstions: Are the strong affinities between HAdV-B7, B14, B55 fibres with DSG2 asociated with severe infection? What are the critical amino acids of fibres of HAdV-B7, B14, B55 binding with DSG2? We have developed recombinant HAdV-B3, B7, B55 expressing fluorescent protein and the novel animal model infected with HAdV-B3. In this study, we compare the affinities of HAdV-B7, B14, B55 and B3 fibres for DSG2 with recombinant fibres and chimeric adenoviruses replaced with different fibres by affinity detection and efficiency analysis of infection. The critical epitopes of fibres binding DSG2 would be predicted by bioinformatics methods and be identified with mutational fibre proteins and adenoviruses with mutational fibre. Finally, the effection and mechanism of different adenovirus fibres on adenovirus pathogenicity will be studied using the cell model of tight junction and the Chinese tree shrew model . This research will not only contribute to a better understanding of the pathogenic mechanism of adenovirus, but also provide a theoretical basis on early warning of high pathogenic adenovirus, and the development of the novel adenovirus vectors, adenovirus vaccines or medicines.
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