鲤春病毒血症病毒诱导氧化应激的发生及其分子机理

Spring viremia of carp (SVC) is an important infectious disease affecting cyprinids, primarily common carp (Cyprinus carpio). The causative agent of SVC is spring viremia of carp virus (SVCV). Currently, the pathogenic mechanisms (s) responsible for SVCV infection are not understood. Oxidative stress plays key role in the progress of many diseases. Oxidative stress also plays a dominant pathogenetic role in microbiology infection. Therefore, Novel therapeutic approaches, targeted to the oxidative stress pathway, were proposed to suppress production of reactive oxygen species, which will be useful for suppression of microbiology-induced damage. Previously, we demonstrate d that the expression of HO-1 was down-regulated during SVCV infection in the EPC cells and in common carp. These results indicated that SVCV infection could induce host oxidative stress, which may contribute to tissue injury in affect fish. But the precise mechanism of oxidative stress induced by SVCV infection and its role in viral pathogenesis is unclear. Therefore, we will focus on the following four questions to reveal the molecular mechanism of oxidative stress induced by viral infection: (ⅰ)Whether the SVCV induced oxidative stress？(ⅱ)which gene of SVCV induced the oxidative stress？(ⅲ)Whether the oxidative stress state of host (ROS) has effect on the infection and replication of SVCV? (ⅳ) How does the host antioxidant defense system (Nrf-ARE pathway) respond to SVCV infection? The results of this project will help to understand the viral pathogenesis. Moreover, the results will provide a novel target for pharmacological modulation of SVCV infection.

鲤春病毒血症（SVC）是由鲤春病毒血症病毒（SVCV）引发的、严重危害鲤科鱼类的传染性疾病。但一直以来，针对感染与致病机理等基础科学的研究甚少。氧化应激参与多种疾病的病理过程，也是微生物感染致的病理机制之一。因而，靶向于氧化应激通路、阻断氧化应激发生的策略成为对抗微生物感染、减少组织损伤的新思路。前期研究发现SVCV感染可下调鲤血红素加氧酶1的表达，降低细胞的抗氧化能力，提示SVCV可诱导机体的氧化应激，但SVCV诱发氧化应激的机制以及氧化应激在SVCV致组织损伤中的作用尚不明确。因此，本项目拟围绕SVCV是否诱导机体的氧化应激，SVCV的哪些基因诱导氧化应激，氧化应激状态对SVCV感染的影响以及Nrf-ARE抗氧化应激信号通路在其中的作用等四个问题展开深入研究，以期揭示SVCV诱导氧化应激的分子机理，从氧化应激角度阐明SVCV的致病机理，为靶向于氧化应激通路的抗SVCV药物开发提供靶标。

鲤春病毒血症（SVC）是由鲤春病毒血症病毒（SVCV）引发的、严重危害鲤科鱼类的传染性疾病。本课题围绕SVCV 是否诱导机体的氧化应激，SVCV 的哪些基因诱导氧化应激，氧化应激状态对SVCV 感染的影响以及Nrf2-ARE 抗氧化应激信号通路在其中的作用等四个问题展开了系统的研究。主要结果如下：（1）从氧化物与抗氧化物水平、氧化-还原相关基因的转录以及氧化损伤等三个方面证实了SVCV感染可诱发氧化应激，揭示氧化应激是SVCV致病的病理机制之一。（2）在细胞水平上证实SVCV感染引发胞内ROS的蓄积，在造成生物大分子氧化损伤的同时，也可激活Nrf2及其下游的抗氧化基因的转录与表达，提高细胞的总抗氧化能力，负调控SVCV的复制。（3）靶向于Nrf2的抗氧化处理可激活Nrf2及其下游效应基因的转录与表达，提高胞内的总抗氧化能力，并显著抑制SVCV的复制，降低病毒滴度。以上研究初步阐明了SVCV感染与细胞抗氧化通路Nrf2-ARE的相互作用，为靶向于氧化应激通路、阻断氧化应激发生的抗病毒药物设计提供了重要依据。