Molecular regulation of immunity to viral infections

病毒感染免疫的分子调节

• 批准号: 9028083
• 负责人: JIN WANG
• 金额: $ 39.63万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-12-01 至 2016-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9028083
• 关键词: Affect; Antibody Response; Autophagocytosis; Autophagosome; B-Cell Development; B-Lymphocytes; Cell Death; Cell Survival; Cells; Development; Down-Regulation; Electron Transport; Future; Gene Expression; Generations; Genes; Human; Immune; Immunity; Immunization; Immunologic Memory; Infection; Influenza; Influenza vaccination; Knowledge; Lead; Life; Lipid Peroxidation; Lung; Maintenance; Measures; Mediating; Membrane Lipids; Memory; Memory B-Lymphocyte; Metabolic; Metabolic Pathway; Mitochondria; Molecular; Mus; Play; Production; Quality Control; Regulation; Role; Signal Pathway; Signal Transduction; Spermidine; Structure of germinal center of lymph node; T memory cell; T-Lymphocyte; Testing; Time; Up-Regulation; Vaccination; Vaccines; Viral; Viral Load result; Virus; Virus Diseases; Work; combat; cytokine; epigenetic regulation; improved; in vivo; influenzavirus; insight; novel; novel strategies; pathogen; programs; public health relevance; research study; response; success; transcription factor

 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.

 描述（由申请人提供）：疫苗接种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疫苗成功预防未来感染至关重要。然而，免疫记忆细胞对疫苗反应持久性的分子机制仍有待阐明。我们发现自噬在小鼠记忆B细胞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细胞显示出升高的基础自噬水平，同时调节自噬起始或自噬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出记忆B细胞的加速细胞死亡，并且当用病毒再次攻击时不能产生保护性二抗应答，导致高病毒载量、广泛的肺破坏和死亡率增加。这表明自噬是病毒特异性记忆B细胞存活所必需的。提出实验来检验促进自噬可以通过保护记忆B细胞来增强疫苗接种对抗病毒感染的功效的假设。本研究拟探讨流感疫苗诱导记忆B细胞主动自噬的机制;流感疫苗诱导记忆B细胞主动自噬保护机制;流感疫苗诱导记忆B细胞主动自噬是否能增强免疫记忆。从长远来看，从这项研究中获得的知识将用于开发新的策略，通过促进人类免疫记忆细胞的产生和维持来提高疫苗对病毒病原体的效力。