传染性法氏囊病强、弱毒侵染宿主细胞的分子机制

Infectious bursal disease (IBD) is an important avian immunosuppressive disease. The very virulent infectious bursal disease virus (vvIBDV) threaten poultry industry more seriously. Very virulent and attenuated strains of IBDV are quite different on biological characteristics, although their genetic and genome background are very similar. Because of poorly understand of the differences and its mechanism between virulent and attenuated strains, the virulent strains were blindly used as hot vaccine for control of IBD in some fields. Although virulent strains provide temporary protection from the infection by IBDV, they induce severe immunosuppression and biosafety risks. In this project, the genome function and its coordination mechanism will be researched, and the three-dimensional structure of very virulent and attenuated IBDV will be reconstructed in order to figure out the molecular and structural basis of genetic variation and virulence enhance of vvIBDV. The host cytomembrane proteins interacted with virulent and attenuated IBDV will be screened from B cell of bursa of Fabricius and chicken embryo fibroblast cell (CEF) respectively, the cell receptors for IBDV will be identified, and the mechanism of attachment to host cell for virulent and attenuated strain will be expounded. The host intracellular proteins of B and CEF cell and the relevant signal pathway interacted with virulent and attenuated IBDV will be illuminated respectively, and the innate immunity and its mechanism involved in the replication of virulent and attenuated strain will be illustrated. Totally, the signaling network involved in the interaction between virulent and attenuated strains and host cells will be analyzed systematically, the molecular mechanism of host cells invasion of IBDV and the relevant differences between virulent and attenuated IBDV will be clarified, which will provide theoretical basis for new vaccines development and the prevention and control of IBD safely and appropriately.

传染性法氏囊病（IBD）是禽类重要的免疫抑制病，超强毒（vvIBDV）对养鸡业危害更严重。IBDV强、弱毒遗传背景及基因组极其相似，但生物学性状完全不同。由于不十分清楚强、弱毒侵染宿主差异及其机制，防疫用疫苗毒力被不断盲目提高，虽然靠对靶细胞的暂时占位效应提供了免疫保护，但却导致严重免疫抑制和生物安全隐患。本研究以vvIBDV及其致弱株为主要研究模型，研究其基因组和功能差异及协同机制，重构病毒粒子结构，揭示IBDV遗传变异的分子及结构基础；筛选强、弱毒与体内B细胞和体外CEF细胞膜中的互作蛋白，鉴定病毒细胞受体，解析强、弱毒株细胞嗜性和入侵细胞差异的分子机制；筛选鉴定强、弱毒与宿主细胞内的互作蛋白及信号通路，解析宿主天然免疫等因素影响强、弱毒复制的分子机制。分析IBDV与宿主互作的主要网络，阐明强、弱毒侵染宿主细胞的分子机制及其差异，为传染性法氏囊病新型疫苗研发及安全合理防控提供理论依据。

鸡传染性法氏囊病（Infectious Bursal Disease, IBD）是由传染性法氏囊病病毒（Infectious Bursal Disease Virus，IBDV）引起的一种主要危害雏鸡的急性、高度接触性、免疫抑制性传染病，被世界动物卫生组织（OIE）列为“影响社会经济的重要疾病”，也是养鸡业必须免疫防控的疫病。IBDV强毒能够导致鸡群发病及60%以上死亡，而衣壳蛋白上与强毒仅有两个氨基酸差异的致弱毒，在体、内外细胞中均能很好复制、不致死鸡并能够诱导免疫保护。研究IBDV强、弱毒侵染宿主细胞的分子机制及其差异，对于认识和解析IBDV强毒致病、弱毒免疫的机理，指导IBDV新型防控策略具有重要意义。.本研究以IBDV超强毒及其致弱株为主要研究对象，以生物学特性差异为切入点，首次在原子水平上解析了强、弱毒粒子结构及其差异，提出了IBDV入侵细胞的分子模型，揭示了强、弱毒之间细胞嗜性差异的结构基础；筛选了IBDV与靶细胞膜上相互作用蛋白，鉴定了CD74为IBDV的细胞吸附受体，进一步明晰了IBDV侵染细胞的分子机制；筛选鉴定了IBDV与靶细胞内相互作用蛋白及信号通路，解析了天然免疫对IBDV感染的限制作用以及IBDV拮抗天然免疫应答的分子机制，发现宿主与病毒互作在IBDV强、弱毒的细胞内复制差异中发挥了重要作用。本研究从病原学、细胞受体、天然免疫三个角度，解析了IBDV强、弱毒侵染宿主细胞的分子机制及差异；有助于深入了解IBDV遗传变异和致病机制，也将为动物疫病新型疫苗研发和安全合理防控研究提供新思路。.本项目申报国家发明专利3项，其中已授权1项。已发表第一标注SCI文章13篇（Journal of Virology 3篇），中文文章9篇；其它标注文章14篇。获得黑龙江省科技进步一等奖1项。项目组成员被评为万人计划科技创新领军人才和科技部中青年科技创新领军人才，毕业研究生12名、博士后1名。打造了一支具有创新活力的禽免疫抑制病研究团队。