Molecular regulation of immunity to viral infections

 描述(申请人提供)：接种疫苗一直是最广泛使用的预防病毒感染的策略。免疫记忆的建立对于预防未来感染的疫苗的成功至关重要。然而，免疫记忆细胞对疫苗的持久反应的分子机制仍有待阐明。我们已经发现，自噬在小鼠记忆B细胞对抗流感病毒感染的长期存活中起着关键作用。与幼稚B细胞和生发中心B细胞相比，记忆B细胞基础自噬水平升高，调节自噬启动或自噬小体成熟的基因表达增加。B细胞自噬缺陷的小鼠在流感免疫后表现为记忆B细胞加速死亡，当病毒再次攻击时不能产生保护性二次抗体反应，导致高病毒载量，广泛的肺破坏和增加的死亡率。这表明自噬是病毒特异性记忆B细胞生存所必需的。有人提议通过实验来验证这样一种假设，即促进自噬可以通过保护记忆B细胞来增强疫苗接种对病毒感染的效力。1)研究流感疫苗诱导记忆B细胞主动自噬的机制；2)探讨自噬在流感病毒疫苗诱导记忆B细胞保护中的作用机制；3)确定诱导自噬是否能增强对流感疫苗的免疫记忆。从长远来看，从这项研究中获得的知识将被用于开发新的策略，通过促进人类免疫记忆细胞的产生和维持来提高针对病毒病原体的疫苗接种的效力。

 DESCRIPTION (provided by applicant): Vaccination has been the most widely used strategy to protect against viral infections. The establishment of immunological memory is critical for the success of vaccines against future infections. However, the molecular mechanisms underlying the persistence of immunological memory cells in response to vaccines remain to be elucidated. We have found that autophagy plays a critical role in the long-term survival of memory B cells against influenza virus infection in mice. Compared to naïve B cells and germinal center B cells, memory B cells display elevated levels of basal autophagy with increased expression of genes that regulate autophagy initiation or autophagosome maturation. Mice with deficiency of autophagy in B cells show accelerated cell death in memory B cells after immunization with influenza, and fail to generate protective secondary antibody responses when re-challenged with the virus, resulting in high viral loads, widespread lung destruction and increased fatality. This suggests that autophagy is required for the survival of virus-specific memory B cells. Experiments are proposed to test the hypothesis that promoting autophagy can enhance the efficacy of vaccination against viral infections through the protection of memory B cells. The following studies are proposed: 1) To determine the mechanisms for active autophagy in memory B cells induced by influenza vaccination; 2) To investigate the mechanisms for autophagy in the protection of memory B cells induced by vaccination against influenza viruses; and 3) To determine whether induction of autophagy can boost immunological memory to influenza vaccination. In the long term, the knowledge gained from the study will be employed to develop novel strategies for boosting the efficacy of vaccination against viral pathogens by promoting the generation and maintenance of immunological memory cells in humans.