Role of gammaHV68 M1 antigen in Vbeta4+ T cell expansion and fibrosis

gammaHV68 M1 抗原在 Vbeta4 T 细胞扩增和纤维化中的作用

基本信息

批准号：
7387671
负责人：
SAMUEL H SPECK
金额：
$ 43.14万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-01-01 至 2012-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7387671
关键词：
Acute Address Affinity Antigens Antiviral Response Ascites B-Lymphocytes Binding Binding Proteins Biochemical CD8B1 gene Cell physiology Cells Chronic Chronic Disease Development Disease Disease Progression Disruption Epitopes Exhibits Failure Fibroblasts Fibrosis Gene Expression Genes Genetic Transcription Grant Herpesviridae Immune Immune response Immune system Immunocompetent Immunocompromised Host Infection Inflammatory Interferons Latent Virus Ligands Light Link Location Lytic Lytic Phase Maintenance Maps Mediating Modeling Molecular Mus Open Reading Frames Organ Outcome Study Pathogenesis Pathology Peptide/MHC Complex Play Poxviridae Production Proteins Reaction Recombinants Regulation Regulatory Element Reporting Resolution Role Sequence Homology Serpins Simplexvirus Site Source Structure Study models Superantigens T-Cell Activation T-Lymphocyte Testing Time Tissues Transcript Ursidae Family Vasculitis Viral Virus Virus Replication Wild Type Mouse Work base cell type chemokine inhibitor/antagonist interferon gamma receptor interferon gamma receptors latent infection mutant novel promoter reactivation from latency response

项目摘要

DESCRIPTION (provided by applicant): Herpesvirus disease pathogenesis is closely linked to host immune status. Murine gammaherpesvirus 68 (?HV68) provides a model for studying the outcome of chronic gammaherpesvirus infection in the immunocompetent versus immunodeficient host. ?HV68 infection of a wild-type mouse results in a limited, acute infection at the site of inoculation, followed by latent, disseminated infection in a variety of tissues and cell types. Although wild-type mice rarely display any virus-related pathology, interferon-gamma receptor- deficient hosts (IFN?R-/-) develop potentially lethal, systemic inflammatory disease. This immune-mediated pathology consists of multi-organ fibrotic tissue damage and vasculitis, associated with chronic reactivation of latent virus and persistent replication. Interestingly, many features of this disease are absent during chronic infection with a ?HV68 mutant lacking the antigen encoded by the M1 open reading frame (ORF) - even though this mutant virus is not impaired for either acute replication or establishment of a latent infection. The M1 antigen, which bears sequence homology to some pox virus serpins (although it lacks critical catalytic residues) and to the ?HV68 secreted high affinity chemokine binding protein M3, has been shown to regulate ?HV68 reactivation from latency. The mechanism by which M1 exerts this effect, and the extent of immune system involvement, is unknown. Throughout the course of latency, the ?HV68 antiviral response is not appreciably stimulated with one notable exception - the significant expansion of V24+ CD8+ T cells. We have recently shown that expression of the M1 antigen is required for this response. This application aims to study the potentially novel mechanism(s) by which the ?HV68 M1 gene product induces V24+ T cell activity, perhaps to self-limit reactivation from latency through expression of IFN-?, and the role such T cells might play in mediating chronic disease in an immunocompromised host. The following 3 aims are proposed: Aim 1: Characterize M1 transcript structure(s) and regulation of M1 gene expression. Aim 2: Define the mechanism of M1-induced V24+ T cell activation and its influence on T cell function. Aim 3: Define the role of M1 and V24+ T cells in regulating ?HV68 reactivation, latency, and virus-induced systemic inflammatory disease.

描述（申请人提供）：疱疹病毒疾病的发病机制与宿主免疫状态密切相关。鼠伽马疱疹病毒 68 (?HV68) 提供了一个模型，用于研究免疫功能正常宿主与免疫缺陷宿主中慢性伽马疱疹病毒感染的结果。野生型小鼠的HV68感染导致接种部位的有限的急性感染，随后在多种组织和细胞类型中出现潜伏的播散性感染。尽管野生型小鼠很少表现出任何与病毒相关的病理，但干扰素γ受体缺陷的宿主（IFN?R-/-）会发展出潜在致命的全身性炎症性疾病。这种免疫介导的病理学包括多器官纤维化组织损伤和血管炎，与潜伏病毒的慢性再激活和持续复制有关。有趣的是，在缺乏 M1 开放阅读框 (ORF) 编码的抗原的 ?HV68 突变体的慢性感染过程中，这种疾病的许多特征不存在——尽管这种突变病毒不会因急性复制或潜伏感染的建立而受到损害。 M1 抗原与一些痘病毒丝氨酸蛋白酶抑制剂（尽管它缺乏关键的催化残基）和 ?HV68 分泌的高亲和力趋化因子结合蛋白 M3 具有序列同源性，已被证明可以调节 ?HV68 从潜伏期的重新激活。 M1 发挥这种作用的机制以及免疫系统参与的程度尚不清楚。在整个潜伏期中，除了一个值得注意的例外——V24+ CD8+ T 细胞的显着扩增，ΔHV68 抗病毒反应并未明显受到刺激。我们最近表明，这种反应需要 M1 抗原的表达。本申请旨在研究 ?HV68 M1 基因产物诱导 V24+ T 细胞活性的潜在新机制，或许是通过表达 IFN-γ 来自我限制潜伏期的重新激活，以及此类 T 细胞在介导免疫功能低下宿主的慢性疾病。提出了以下 3 个目标：目标 1：表征 M1 转录物结构和 M1 基因表达的调控。目标 2：明确 M1 诱导 V24+ T 细胞激活的机制及其对 T 细胞功能的影响。目标 3：明确 M1 和 V24+ T 细胞在调节 ?HV68 重新激活、潜伏期和病毒诱导的全身炎症性疾病中的作用。