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

• 批准号: 8010967
• 负责人: SAMUEL H SPECK
• 金额: $ 38.5万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 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/8010967
• 关键词: Acute; Affinity; Animals; Antigens; Antiviral Response; Binding Proteins; Budgets; CD8B1 gene; Cell physiology; Chronic; Chronic Disease; Development; Disease; Equipment; Fibrosis; Funding; Gene Expression; HIV; Hepatitis C virus; Herpesviridae; Human; Human Herpesvirus 8; Human Virus; Immune; Immune system; Immunocompetent; Immunocompromised Host; Individual; Infection; Inflammatory; Interferons; Latent Virus; Left; Link; Lymphocytic choriomeningitis virus; Mediating; Molecular Biology; Mus; Open Reading Frames; Organ; Outcome Study; Pathogenesis; Pathology; Phenotype; Play; Poxviridae; Proteins; Reaction; Reagent; Records; Regulation; Research; Role; Running; Sequence Homology; Serpins; Site; Structure; Study models; System; T cell response; T-Cell Activation; T-Lymphocyte; Tissues; Transcript; Ursidae Family; Vasculitis; Virus; Virus Diseases; Wild Type Mouse; Work; cell type; chemokine; cost; exhaust; exhaustion; gammaherpesvirus; genetic profiling; in vivo; instrument; interest; interferon gamma receptor; interferon gamma receptors; latent infection; molecular marker; mouse model; mutant; novel; premature; prevent; reactivation from latency; response; seal; tissue culture; vaccination strategy

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（由申请人提供）：疱疹病毒疾病发病机理与宿主免疫状态密切相关。鼠伽马犬68（？hv68）提供了一个模型，用于研究免疫功能与免疫缺陷宿主中慢性γ掌病毒感染的结果。野生型小鼠感染的感染会导致接种部位的急性感染有限，然后在多种组织和细胞类型中进行潜在的，散布的感染。尽管野生型小鼠很少表现出任何与病毒相关的病理学，但干扰素 - γ受体缺乏宿主（IFN？r - / - ）会产生潜在的致命性，全身性炎症性疾病。这种免疫介导的病理包括多器官纤维化组织损伤和血管炎，与潜在病毒的慢性重新激活和持续复制有关。有趣的是，这种疾病的许多特征在慢性感染过程中缺乏缺乏由M1开放阅读框（ORF）编码的抗原的突变体（ORF） - 即使该突变病毒因急性复制或降低潜伏感染而受到损害。 M1抗原与某些痘病毒丝氨酸具有序列同源性（尽管缺乏关键的催化残基），并且已证明对hv68分泌的高亲和趋化蛋白M3分泌的HV68可以调节延迟的HV68重新激活。 M1发挥这种作用以及免疫系统参与程度的机制尚不清楚。在整个延迟过程中，没有一个值得注意的例外 - V24+ CD8+ T细胞的显着扩展。我们最近表明，此反应需要M1抗原的表达。该应用旨在研究？HV68 M1基因产物诱导V24+ T细胞活性的潜在新型机制，也许是从延迟到表达IFN-的自我限制重新激活，并且这些T细胞在免疫敏感宿主中介导慢性疾病的作用可能在介导慢性病中起作用。提出了以下3个目标：目标1：表征M1转录本结构和M1基因表达的调节。 AIM 2：定义M1诱导的V24+ T细胞激活的机制及其对T细胞功能的影响。目标3：定义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性炎症性疾病中的作用。