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是免疫球蛋白基因的体细胞超突变和类别转换重组所必需的胞苷脱氨酶。除了在脊椎动物适应性免疫系统中介导抗体多样化的作用外，我们最近还表明AID还介导一种形式的宿主对病毒感染的反应。我们已经发现，AID在原代B细胞中响应于转化逆转录病毒（transforming retrovirus，ADM-MLV）的病毒感染而被特异性诱导。作为AID诱导的结果，感染的宿主细胞的增殖被显著限制。这在组织培养感染和体内都是正确的：我们发现，当移植到野生型受体中时，艾滋病缺陷型Abelson肿瘤比野生型肿瘤更具侵略性。这些实验描述了一种新的现象，具有重要意义的主机在体外和体内的抗病毒反应。该建议旨在研究这种新型病毒感染反应的分子机制。具体而言，我们建议：a）确定AID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重要的AID残留物。如果需要催化活性，我们将研究胞苷脱氨酶损伤下游可能导致宿主增殖丧失的各种类型的事件。如果不需要催化活性，我们将研究AID结合核酸的能力（与催化反应的能力不同）是否是表型所必需的。B）了解病毒诱导的AID是如何调节的。我们将对AID诱导是宿主抗病毒反应的一部分的病毒类型进行编目，确定这是主动抗病毒反应的细胞类型，并确定导致宿主细胞中AID上调的途径。总之，这些实验将描绘这种新的宿主对病毒感染的反应的作用机制，此外，它们将确定导致这种反应的信号通路。