CMV-encoded TNF receptor and viral dissemination

CMV 编码的 TNF 受体和病毒传播

• 批准号: 7876903
• 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/7876903
• 关键词: Abbreviations; Adult; 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(申请人提供)：巨细胞病毒(CMV)感染广泛，通常是无症状的。这种病毒在宿主中建立了终生潜伏期，并在怀孕期间从母亲传播给胎儿时成为主要病原体，并在免疫受损的宿主中传播。CMV病的风险由多种宿主和病毒因素决定，但目前尚不清楚特定的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经降低了CMV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。巨细胞病毒疫苗目前还不能用于预防免疫受损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(UL131-UL150)的人CMV基因。这些基因在实验室适应菌株中缺失，但在所有临床分离株中都存在；因此，被认为在宿主中起致病作用。其中一些基因编码细胞因子和趋化因子，可能会干扰宿主的免疫反应。我们从多个人类样本中测定了UL144(TNF1受体基因)、UL146和UL147(1个趋化因子基因)的序列，并确定了它们的多态性。在两项队列研究中，我们还发现UL144基因的多态与先天性巨细胞病毒感染的结局相关。最近的研究表明，UL144的胞外区与B和T淋巴细胞衰减剂相互作用，并在体外抑制T细胞的增殖。UL144还激活了核因子-B，导致趋化因子CCL22的表达增强，CCL22是Th2淋巴细胞的趋化诱导剂。这些研究表明，UL144可能通过影响Th1/Th2应答而干扰宿主的免疫监视，这可能有助于CMV的传播。我们的假设是UL144在允许CMV在宿主中传播方面起到了作用。由于信号和Th1反应激活的不同，某些UL144基因可能比其他类型诱导的宿主细胞介导的免疫效果更差，从而将免疫反应转向Th2反应。我们提出了以下具体目标：1)确定UL144激活核因子-的分子机制的某些方面：B.我们将确定UL144的哪个结构域在信号转导中起重要作用，并确定与UL144相互作用的蛋白质。2)体外检测UL144对Th1/Th2应答的影响。采用共培养系统，检测UL144基因分型对Th1/Th2淋巴细胞反应和细胞因子产生的影响。公共卫生相关性：我们希望提供新的视角，更好地理解UL144激活核因子-B的机制。我们还将深入了解UL144不同基因型在信号传递方面的差异，以及它们影响Th1/Th2反应的能力。了解UL144在允许病毒传播和免疫逃避中的作用，可能会开启药物和疫苗开发的新战略。