Role of Viral Chemokine Receptors in Cytomegalovirus Latency.

病毒趋化因子受体在巨细胞病毒潜伏期中的作用。

• 批准号: 8235473
• 负责人: Rhonda D Cardin
• 金额: $ 35.84万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-05 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8235473
• 关键词: Acquired Immunodeficiency Syndrome; Adoptive Transfer; Apoptosis; Biological Assay; Bone Marrow; Bone Marrow Transplantation; Boxing; Cell Line; Cell Lineage; Cell Survival; Cells; Complement; Complication; Coupled; Cytomegalovirus; Cytomegalovirus Infections; DNA; Data; Defect; Development; Disease; GTP-Binding Proteins; Goals; Herpesviridae; Homologous Gene; Human; ITGAM gene; Immunocompromised Host; In Vitro; Individual; Infection; Integration Host Factors; Knowledge; Label; Lead; Letters; Life; Maintenance; Mediating; Methods; Microarray Analysis; Morbidity - disease rate; Mus; Myelogenous; Myeloid Cells; Outcome; Pathogenesis; Patients; Population; Prevention; Public Health; Research; Resources; Role; Signal Pathway; Signal Transduction; Spleen; Testing; Transgenic Mice; Transplant Recipients; Viral; Viral Genome; Virus; Work; base; beta-Chemokines; cell type; chemokine receptor; in vitro Assay; in vivo; innovation; latent infection; monocyte; mortality; mutant; neonate; novel therapeutics; pathogen; prevent; progenitor; reactivation from latency; therapeutic development; viral DNA; virology

DESCRIPTION (provided by applicant): Reactivation of Human Cytomegalovirus (HCMV) from latency is the most common infectious complication in bone marrow transplant patients, with significant morbidity and mortality. Very little is known about the viral/host interactions governing the establishment and maintenance of long term HCMV infection. The long-term goal is to identify the viral and host mechanisms that lead to the development of CMV latency. The objective of this proposal is to determine the role of the CMV-encoded chemokine receptors in the establishment of latency in progenitor myeloid lineage cells and to identify the host signaling pathways that promote CMV establishment of latency. The central hypothesis is that the CMV-encoded chemokine receptors activate host signaling pathways which aid in the establishment of latency during in vivo infection. Project Summary: Our hypothesis is based on strong preliminary data which demonstrates that murine CMV (MCMV) lacking M33 does not efficiently establish latent infection and that M33-deficient viruses which express the HCMV-encoded chemokine receptors, UL33 or US28, complements this latency defect in vivo. Three specific aims will be pursued: 1) Identify the myeloid lineage cell type which requires M33 for the establishment and/or maintenance of CMV latency in vivo, 2) Identify the mechanisms underlying the role of M33 during infection in monocytes, and 3) Identify the M33-mediated signaling pathway (s) required for establishment and/or maintenance of CMV latency. This aim will utilize specific M33 mutant viruses coupled with microarray analysis to identify signaling pathways which are modulated by M33 and US28. The approach is innovative, and uses a multifaceted approach to identify the host and viral factors involved in the establishment and/or maintenance of CMV latency in myeloid lineage cells. The proposed research is significant, because it is expected to lead to the development of therapeutic strategies aimed at preventing CMV latency and complications due to reactivation of latent CMV. Relevance to Public Health: The new knowledge obtained will lead to the prevention of CMV latency and reactivation in immunocompromised patients, such transplant patients, neonates, and AIDS patients, where CMV infection leads to significant morbidity and mortality. PUBLIC HEALTH RELEVANCE: Relevance to Public Health: The new knowledge obtained will lead to the prevention of CMV latency and reactivation in immunocompromised patients, such as transplant patients, neonates, and AIDS patients, where CMV infection leads to significant morbidity and mortality.

描述（由申请人提供）：潜伏期中人类巨细胞病毒（HCMV）的重新激活是骨髓移植患者中最常见的感染并发症，具有明显的发病率和死亡率。关于长期HCMV感染的建立和维持的病毒/宿主相互作用知之甚少。长期目标是确定导致CMV潜伏期发展的病毒和宿主机制。该提案的目的是确定CMV编码的趋化因子受体在祖细胞髓样谱系细胞中潜伏期建立潜伏期中的作用，并确定促进CMV延迟的宿主信号传导途径。中心假设是CMV编码的趋化因子受体激活宿主信号通路，这有助于在体内感染过程中建立潜伏期。项目摘要：我们的假设基于强大的初步数据，该数据表明缺乏M33的鼠CMV（MCMV）并不能有效地建立潜在的感染，并且表达HCMV已编码的趋化因子受体UL33或US28的M33缺陷病毒，会在VIVO中互补。将追求三个具体目的：1）确定需要M33来建立和/或体内CMV潜伏期的M33，2）确定M33在单核细胞中感染过程中M33作用的机制，以及3）确定M33介导的信号通路（s）所需的comv（s）。该目的将利用特定的M33突变病毒，再加上微阵列分析来识别由M33和US28调节的信号通路。该方法具有创新性，并使用多方面的方法来识别在髓样谱系细胞中CMV潜伏期建立和/或维持CMV潜伏期所涉及的宿主和病毒因素。拟议的研究非常重要，因为预计它将导致旨在防止CMV潜伏期和由于潜在CMV重新激活而发展的治疗策略。与公共卫生的相关性：获得的新知识将导致预防免疫功能低下的患者（例如移植患者，新生儿和艾滋病患者）的CMV潜伏期和重新激活，其中CMV感染会导致明显的发病率和死亡率。 公共卫生相关性：与公共卫生的相关性：获得的新知识将导致预防免疫功能低下患者的CMV潜伏期和重新激活，例如移植患者，新生儿和AIDS患者，在那里CMV感染会导致明显的发病率和死亡率。