c-Src激酶-整合素α4β1分子模块在传染性法氏囊病病毒感染B淋巴细胞过程中的作用及分子机制研究

Infectious bursal disease virus (IBDV), the causative agent of infectious bursal disease (IBD), mainly destroys the immature B lymphocyte resulting in severe immunosuppression. However, the mechanism by which IBDV invades and infects B cells remains elusive. c-Src kinase is a member belonging to a family of non-receptor protein tyrosine kinase, and together with adhesion molecule integrins, plays key roles in the regulation of viral strategies for evading host cells. In this study, we aim to explore the roles of c-Src-integrin α4β1 module in IBDV infection of B cells. We will investigate the c-Src kinase dynamic phosphorylation in B cells upon IBDV infection over a time course. The correlation between the c-Src kinase phosphorylation induced and the viral virulence will be established. Furthermore, the roles of c-Src kinase-integrin α4β1 module in the regulation of PI3K-Akt signaling pathway and cytoskeleton reorganization during IBDV infection will be examined. Together, these data will for the first time provide new insights into the how IBDV invades and establishes infection in B cells, and lead to the development of pharmacological interventions and clinical strategies for treatment of IBDV induced immunosuppression.

传染性法氏囊病病毒（IBDV）主要侵染雏鸡法氏囊内的未成熟B淋巴细胞，引起严重的免疫抑制，然而IBDV侵入宿主B淋巴细胞及其建立感染的分子机制尚不清楚。c-Src是一种非受体型蛋白酪氨酸激酶，参与介导整合素信号的转导过程而被激活，在病毒侵入宿主细胞过程中发挥重要功能。本项目首先从体外建立的B淋巴细胞感染模型着手，研究IBDV感染与B淋巴细胞内c-Src激酶磷酸激酶活性水平动态变化之间的关系；其次，体内实验研究IBDV强弱毒株的感染与c-Src激酶磷酸化之间的关系，明确c-Src激酶磷酸激酶活性水平与IBDV毒力的相关性；最后，进一步探讨c-Src激酶-整合素α4β1分子模块对胞内关键信号通路PI3K-Akt的调控和对细胞骨架重排的影响及其分子机制。这将为解析和阐明IBDV导致的免疫抑制机制提供新理论，并为进一步开发用于IBD防治的小分子药物提供新靶点。

鸡传染性法氏囊病（IBD）是以免疫抑制为特征的烈性传染病，对养禽业危害极大。传染性法氏囊病病毒（IBDV）是引起鸡传染性法氏囊病的致病因子，揭示IBDV侵入细胞的分子机制是开发防控IBD新技术和新方法的前沿理论问题。本项目以细胞模型为主辅以动物实验，阐明了宿主因子c-Src激酶磷酸化水平在IBDV侵入宿主细胞过程中的动态变化规律；揭示了IBDV侵入宿主细胞的信号传导机制，特别是将已报道的IBDV细胞受体分成两类进行探讨与c-Src激酶磷酸化及病毒侵入的关系，做出一类IBDV受体介导IBDV的粘附，另一类IBDV受体介导信号转导的推论，完善了原有对病毒受体的理解；建立了IBDV通过整合素α4β1激活胞内c-Src-PI3K/Akt-RhoA GTP酶-细胞骨架重排的信号转导通路而侵入宿主细胞的前反馈模型。这些研究结果一定程度上揭示了IBDV侵入宿主细胞的细胞生物学特征，为研制抑制IBDV侵入的药物提供了靶点，也为开发IBDV治疗药物提供了理论支持。