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: 8680118
• 负责人: Rhonda D Cardin
• 金额: $ 34.29万
• 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/8680118
• 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.

描述（由申请方提供）：人巨细胞病毒（HCMV）潜伏期再激活是骨髓移植患者最常见的感染性并发症，具有显著的发病率和死亡率。很少有人知道病毒/宿主的相互作用，建立和维持长期HCMV感染。长期目标是确定导致CMV潜伏期发展的病毒和宿主机制。本提案的目的是确定CMV编码的趋化因子受体在祖细胞髓系细胞中建立潜伏期的作用，并确定促进CMV建立潜伏期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传导途径，这有助于在体内感染期间建立潜伏期。项目概要：我们的假设是基于强有力的初步数据，这些数据表明缺乏M33的鼠巨细胞病毒（MCMV）无法有效建立潜伏感染，而表达巨细胞病毒编码的趋化因子受体UL 33或US 28的M33缺陷病毒可以补充体内的这种潜伏缺陷。将追求三个具体目标：1）鉴定需要M33以建立和/或维持体内CMV潜伏期的髓系细胞类型，2）鉴定单核细胞感染期间M33作用的潜在机制，和3）鉴定建立和/或维持CMV潜伏期所需的M33介导的信号传导途径。这一目标将利用特定的M33突变病毒与微阵列分析相结合，以确定由M33和US 28调节的信号通路。该方法是创新的，并且使用多方面的方法来鉴定参与骨髓谱系细胞中CMV潜伏期的建立和/或维持的宿主和病毒因素。拟议的研究是重要的，因为它有望导致旨在预防CMV潜伏期和由于潜伏CMV再激活引起的并发症的治疗策略的发展。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中的CMV潜伏期和再激活，例如移植患者、新生儿和AIDS患者，其中CMV感染导致显著的发病率和死亡率。