Cytomegalovirus infection of blood vessels

描述（由申请人提供）： 人巨细胞病毒（HCMV）是免疫功能低下个体最常见的机会性感染之一，包括器官移植受者和艾滋病患者。此外，HCMV也被认为是血管疾病发病机制中的可能致病因素，包括动脉粥样硬化、血管成形术后的动脉再狭窄和实体器官移植血管硬化。 主动脉中的CMV感染在病毒相关血管疾病的发展中起关键作用。 大血管可以是急性和潜伏性病毒感染的部位。血管中的持续感染通过（a）产生内皮的局部损伤和损伤，（B）上调诱导炎症反应的细胞粘附分子和趋化因子的表达，和（c）增强平滑肌细胞的增殖和迁移而促进血管疾病的发展。保护患者，特别是那些免疫功能低下的患者，免于发生CMV相关的血管疾病，需要消除血管中的HCMV感染并阻断这些组织中的病毒复制。了解巨细胞病毒在血管中感染的机制将为巨细胞病毒相关血管疾病的治疗和预防提供新的思路。 使用小鼠巨细胞病毒（MCMV）作为模型系统，拟议的研究是确定所需的CMV复制在主动脉中的病毒基因，并研究这些病毒的决定因素在支持CMV感染的血管壁的功能。我们最近已经产生了一个池MCMV突变体，含有转座子序列。我们还分离出了一种病毒突变体，它在主动脉中的复制减弱，并且在诱导病毒相关的血管疾病（包括急性动脉炎和动脉粥样硬化）方面有缺陷。 在拟议的研究中，小鼠将被病毒突变体感染，而那些在主动脉中复制缺陷的突变体将被分离出来。将研究这些突变体的致病性，并鉴定突变的基因。此外，将研究所鉴定的病毒决定簇如何在支持主动脉中的MCMV感染和促进血管疾病中起作用的机制。这些研究将导致主动脉感染的病毒决定因素的识别和这些基因在CMV相关血管疾病的发展中的功能的调查。了解血管中CMV感染的机制将有助于开发治疗和预防CMV相关血管疾病以及病毒全身感染的新策略。

DESCRIPTION (provided by applicant): Human cytomegalovirus (HCMV) causes one of the most common opportunistic infections in immunocompromised individuals, including organ transplant recipients and AIDS patients. Moreover, HCMV has also been implicated as a possible etiologic factor in the pathogenesis of vascular diseases, including atherosclerosis, arterial restenosis following angioplasty, and solid organ transplant vascular sclerosis. CMV infection in the aorta plays a key role in the development of viral-associated vascular diseases. The great vessels can be the sites for both acute and latent viral infections. Ongoing infections in the vessels facilitate the development of vascular diseases by (a) generating local lesions and injury of the endothelium, (b) up-regulating the expression of cell adhesion molecules and chemokines that induce inflammatory response, and (c) enhancing proliferation and migration of smooth muscle cells. Protection of patients, especially those who are immunocompromised, from developing CMV-associated vascular diseases requires eliminating HCMV infection from the blood vessels and blocking viral replication in these tissues. Understanding the mechanism of CMV infections in the vessels will provide insight into treatment and prevention of CMV-associated vascular diseases. Using murine CMV (MCMV) as a model system, the proposed study is to identify the viral genes required for CMV replication in the aorta and to study the functions of these viral determinants in supporting CMV infections in the vascular wall. We have recently generated a pool of MCMV mutants that contain a transposon sequence. We have also isolated a viral mutant that is attenuated in replication in the aorta and is defective in inducing viral-associated vascular diseases including acute arteritis and atherosclerosis. In the proposed research, mice will be infected with viral mutants and those mutants that are defective in replicating in the aorta will be isolated. The pathogenecity of these mutants will be studied, and the genes that are mutated will be identified. Moreover, the mechanism of how the identified viral determinants function in supporting MCMV infections in the aorta and promoting vascular diseases will be investigated. These studies will lead to the identification of viral determinants for infection in the aorta and the investigation of the functions of these genes in the development of CMV-associated vascular diseases. Understanding the mechanism of CMV infection in blood vessels will facilitate the development of novel strategies for treatment and prevention of CMV-associated vascular diseases as well as viral systemic infections.