The role of AID protein in the host response to viral infection

AID蛋白在宿主病毒感染反应中的作用

• 批准号: 7135588
• 负责人: F. NINA Papavasiliou
• 金额: $ 29.58万
• 依托单位: ROCKEFELLER UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-05-15 至 2009-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7135588
• 关键词: aminohydrolases; cytidine; infection; lead; proteins; role

DESCRIPTION (provided by applicant): AID is a cytidine deaminase necessary for somatic hypermutation and class switch recombination of immunoglobulin genes. In addition to this role in mediating antibody diversification within the vertebrate adaptive immune system, we have recently shown that AID also mediates a form of host response against viral infection. We have found that AID is specifically induced in primary B cells in response to viral infection by a transforming retrovirus (Abl-MLV). As a result of AID induction the proliferation of infected host cells is significantly restricted. This is true both in tissue culture infections as well as in vivo: we found that AID-deficient Abelson tumours are far more aggressive than their wildtype counterparts, when transplanted into wildtype recipients. These experiments describe a novel phenomenon with important implications for the host antiviral response both in vitro and in vivo. This proposal aims to investigate the molecular mechanism underlying this novel response to viral infection. Specifically, we propose to: a) Determine the mechanism by which AID restricts the proliferation of virally infected cells. We will first determine the residues of AID that are important in the host antiviral response. If catalytic activity is required, we will investigate various types of events downstream a cytidine deaminase lesion which could result in loss of proliferation in the host. If catalytic activity is not required we will investigate whether the ability of AID to bind nucleic acid, which is distinct from the ability to catalyze the reaction, is necessary for the phenotype. b) Understand how virally-induced AID is regulated. We will catalog the types of viruses for which AID induction is part of the host antiviral response, determine the types of cells for which this is an active anti-viral response and identify the pathways which lead to AID upregulation in the host cell. Together, these experiments will delineate the mechanism of action of this novel host response to viral infection and in addition, they will determine the signaling pathways which lead to this response.

描述（由申请人提供）：AID是一种胞化酶脱氨酶，是免疫球蛋白基因的体细胞超成名和类转换重组所必需的。除了在介导脊椎动物适应性免疫系统中介导抗体多样化的作用外，我们最近表明，援助还介导了一种针对病毒感染的宿主反应形式。我们发现，通过转化的逆转录病毒（ABL-MLV），在原代B细胞中特别诱导了AID。由于辅助诱导，受感染宿主细胞的增殖受到了显着限制。在组织培养感染和体内都如此：我们发现，当移植到Wildtype接受者中时，缺乏辅助的Abelson肿瘤比其野生型肿瘤更具侵略性。这些实验描述了一种新型现象，对体外和体内的宿主抗病毒反应具有重要意义。该建议旨在研究这种对病毒感染反应的新反应的基本机制。具体而言，我们建议：a）确定辅助限制病毒感染细胞增殖的机制。我们将首先确定在宿主抗病毒反应中很重要的援助残留物。如果需要催化活性，我们将调查胞苷脱氨酶病变下游的各种类型的事件，这可能导致宿主中的增殖丧失。如果不需要催化活性，我们将研究辅助结合核酸的能力（与催化反应能力不同）是否是表型所必需的。 b）了解如何调节病毒引起的援助。我们将分类辅助诱导是宿主抗病毒反应的一部分的病毒类型，确定其为活性抗病毒反应的细胞类型，并确定导致宿主细胞中上调的途径。总之，这些实验将描绘出这种新型宿主对病毒感染反应的作用机理，此外，它们将确定导致这种反应的信号传导途径。