CMV-encoded TNF receptor and viral dissemination

CMV 编码的 TNF 受体和病毒传播

• 批准号: 7640222
• 负责人: Ravit Boger
• 金额: $ 8.2万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-19 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7640222
• 关键词: Abbreviations; Affect; Antiviral Therapy; Attenuated; CMV glycoprotein B; Cell Line; Cells; Cellular Immunity; Chemotactic Factors; Clinical; Co-Immunoprecipitations; Coculture Techniques; Cohort Studies; Cytomegalovirus; Cytomegalovirus Infections; Cytomegalovirus Vaccines; DNA Vaccines; Data; Disease; Fetus; Genes; Genetic; Genetic Polymorphism; Genotype; Helper-Inducer T-Lymphocyte; Herpesviridae; Human; Immune; Immune response; Immunocompromised Host; Immunologic Surveillance; In Vitro; Infant; Infection; Institute of Medicine (U.S.); LMP1; Laboratories; Lymphocyte; Mediator of activation protein; Molecular; Morbidity - disease rate; Mothers; Newborn Infant; Open Reading Frames; Outcome; Pathogenesis; Pharmaceutical Preparations; Play; Population; Pregnancy; Production; Proteins; Receptor Gene; Regulatory T-Lymphocyte; Risk; Role; Sampling; Signal Transduction; Signaling Protein; System; T-Cell Proliferation; T-Lymphocyte; TNF Receptor-Associated Factors; Testing; Toxic effect; Transfection; Tumor Necrosis Factor Receptor; Tumor Necrosis Factor-alpha; Tumor Necrosis Factors; Viral; Virus; Work; chemokine; congenital cytomegalovirus; congenital infection; cytokine; high voltage electron microscopy; insight; interest; macrophage-derived chemokine; mortality; pathogen; prevent; public health relevance; receptor; research study; response; vaccine candidate; vaccine development; virus host interaction

DESCRIPTION (provided by applicant): Cytomegalovirus (CMV) infection is widespread and is usually asymptomatic. The virus establishes lifelong latency in the host and becomes a major pathogen when transmitted during pregnancy from mother to fetus, and in immunocompromised hosts. The risk of CMV disease is determined by multiple host and viral factors, but it is unknown whether specific CMV strains are more likely to reactivate and disseminate than others. Currently available antiviral therapies have decreased morbidity and mortality of CMV disease but are limited by toxicities and by variable efficacy in established disease. CMV vaccine is currently not available to prevent congenital infection or disease in immunocompromised hosts. We have been studying human CMV genes located in the UL/b' region of the virus (UL131-UL150). These genes are deleted in laboratory adapted strains but exist in all clinical isolates; therefore, thought to play a pathogenesis role in the host. Some of these genes encode for cytokines and chemokines that may interfere with host immune responses. We sequenced UL144 (TNF1 receptor gene), UL146 and UL147 (1 chemokine genes) from multiple human samples, and defined their polymorphisms. We also showed in two cohort studies that polymorphisms in UL144 correlate with outcome of congenital CMV infection. Recent studies show that the ectodomain of UL144 interacts with the B and T cell lymphocyte attenuator and inhibits T cell proliferation in vitro. UL144 also activates NF-:B, resulting in enhanced expression of the chemokine CCL22, a chemoattractant for Th2 lymphocytes. These studies suggest that UL144 plays a role in interference with host immune surveillance possibly via effects on Th1/Th2 responses, which may help CMV to disseminate. Our hypothesis is that UL144 has a role in allowing CMV to disseminate in the host. Certain UL144 genotypes may elicit less effective host cell mediated immunity than others because of differences in signaling and in activation of Th1 responses, diverting the immune response towards a Th2 response. We propose the following specific aims: 1) to determine some aspects of the molecular mechanisms by which UL144 activates NF-:B. We will determine which domain of UL144 is important in signaling, and identify proteins that interact with UL144. 2) To determine the effects of UL144 on Th1/Th2 responses in vitro. Using co-culture system the effects of UL144 genotypes on Th1/Th2 lymphocyte responses and cytokine production will be determined. PUBLIC HEALTH RELEVANCE: We hope to provide new perspectives and better understanding of the mechanisms by which UL144 activates NF- :B. We will also provide insight into the differences between UL144 genotypes in their signaling and their ability to affect Th1/Th2 responses. Understanding the role of UL144 in allowing viral dissemination and immune evasion, may open a new strategy for drug and vaccine development.

描述（由申请人提供）：巨细胞病毒（CMV）感染广泛且通常无症状。该病毒在宿主体内建立终生潜伏期，并在怀孕期间从母亲传播给胎儿以及免疫功能低下的宿主时成为主要病原体。 CMV 疾病的风险由多种宿主和病毒因素决定，但尚不清楚特定的 CMV 毒株是否比其他毒株更有可能重新激活和传播。目前可用的抗病毒疗法已降低了 CMV 疾病的发病率和死亡率，但受到毒性和对已确定疾病的不同疗效的限制。 CMV 疫苗目前无法用于预防免疫功能低下宿主的先天性感染或疾病。我们一直在研究位于病毒 UL/b' 区域 (UL131-UL150) 的人类 CMV 基因。这些基因在实验室适应性菌株中被删除，但存在于所有临床分离株中；因此，认为在宿主中发挥发病机制作用。其中一些基因编码可能干扰宿主免疫反应的细胞因子和趋化因子。我们对多个人类样本中的 UL144（TNF1 受体基因）、UL146 和 UL147（1 种趋化因子基因）进行了测序，并定义了它们的多态性。我们还在两项队列研究中表明，UL144 的多态性与先天性 CMV 感染的结果相关。最近的研究表明，UL144 的胞外域与 B 细胞和 T 细胞淋巴细胞衰减蛋白相互作用，并在体外抑制 T 细胞增殖。 UL144 还可激活 NF-:B，从而增强趋化因子 CCL22（Th2 淋巴细胞的趋化剂）的表达。这些研究表明，UL144 可能通过影响 Th1/Th2 反应来干扰宿主免疫监视，这可能有助于 CMV 传播。我们的假设是 UL144 在允许 CMV 在宿主中传播方面发挥着作用。由于信号传导和 Th1 反应激活方面的差异，某些 UL144 基因型可能比其他基因型引发的宿主细胞介导的免疫效果较差，从而将免疫反应转向 Th2 反应。我们提出以下具体目标：1) 确定 UL144 激活 NF-:B 分子机制的某些方面。我们将确定 UL144 的哪个结构域对信号传导很重要，并鉴定与 UL144 相互作用的蛋白质。 2) 确定 UL144 对体外 Th1/Th2 反应的影响。使用共培养系统，将确定 UL144 基因型对 Th1/Th2 淋巴细胞反应和细胞因子产生的影响。公共健康相关性：我们希望提供新的视角并更好地理解 UL144 激活 NF-:B 的机制。我们还将深入了解 UL144 基因型之间的信号传导差异及其影响 Th1/Th2 反应的能力。了解 UL144 在允许病毒传播和免疫逃避方面的作用，可能会为药物和疫苗开发开辟新策略。