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: 8867123
• 负责人: Rhonda D Cardin
• 金额: $ 19.71万
• 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 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8867123
• 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（由申请人提供）：人类巨细胞病毒（HCMV）潜伏期的重新激活是骨髓移植患者中最常见的感染并发症，具有显着的发病率和死亡率。对于控制长期 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。本提案的目的是确定 CMV 编码的趋化因子受体在祖骨髓系细胞潜伏期建立中的作用，并确定促进 CMV 潜伏期建立的宿主信号通路。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。项目摘要：我们的假设基于强有力的初步数据，该数据表明，缺乏 M33 的鼠 CMV (MCMV) 不能有效地建立潜伏感染，而表达 HCMV 编码趋化因子受体 UL33 或 US28 的 M33 缺陷病毒可以在体内补充这种潜伏缺陷。将追求三个具体目标：1) 鉴定需要 M33 来建立和/或维持体内 CMV 潜伏期的骨髓谱系细胞类型，2) 鉴定 M33 在单核细胞感染过程中的作用机制，以及 3) 鉴定建立和/或维持 CMV 潜伏期所需的 M33 介导的信号通路。这一目标将利用特定的 M33 突变病毒与微阵列分析相结合来识别受 M33 和 US28 调节的信号通路。该方法具有创新性，采用多方面的方法来识别参与骨髓系细胞 CMV 潜伏期建立和/或维持的宿主和病毒因子。拟议的研究意义重大，因为它预计将导致治疗策略的发展，旨在预防巨细胞病毒潜伏期和由于潜伏巨细胞病毒重新激活而引起的并发症。与公共卫生的相关性：所获得的新知识将有助于预防免疫功能低下患者（例如移植患者、新生儿和艾滋病患者）的巨细胞病毒潜伏期和再激活，这些患者中巨细胞病毒感染会导致显着的发病率和死亡率。