Cytomegalovirus infection of blood vessels

描述(由申请人提供)： 人巨细胞病毒(HCMV)是包括器官移植受者和艾滋病患者在内的免疫受损人群中最常见的机会性感染之一。此外，HCMV也被认为是血管疾病的可能病因，包括动脉粥样硬化、血管成形术后动脉再狭窄和实体器官移植血管硬化症。主动脉中的巨细胞病毒感染在病毒相关性血管疾病的发展中起着关键作用。大血管可能是急性和潜伏病毒感染的场所。血管持续感染通过以下方式促进血管疾病的发展：(A)引起局部损伤和内皮损伤，(B)上调细胞黏附分子和趋化因子的表达，诱导炎症反应，以及(C)促进平滑肌细胞的增殖和迁移。为了保护患者，特别是那些免疫功能低下的患者，避免发生巨细胞病毒相关的血管疾病，需要消除血管中的巨细胞病毒感染，并阻止这些组织中的病毒复制。了解CMV在血管中的感染机制将有助于CMV相关血管疾病的治疗和预防。本研究以小鼠巨细胞病毒(MCMV)为模型系统，旨在确定CMV在主动脉中复制所需的病毒基因，并研究这些病毒决定簇在支持血管壁上CMV感染中的作用。我们最近产生了一个含有转座子序列的MCMV突变体。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，在引发病毒相关血管疾病方面存在缺陷，包括急性动脉炎和动脉粥样硬化。在这项拟议的研究中，小鼠将被感染病毒突变体，那些在主动脉复制有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，已确定的病毒决定因素如何在支持主动脉中的MCMV感染和促进血管疾病方面发挥作用的机制将被调查。这些研究将导致确定主动脉感染的病毒决定因素，并调查这些基因在巨细胞病毒相关血管疾病发展中的功能。了解巨细胞病毒在血管中的感染机制将有助于开发新的治疗和预防巨细胞病毒相关血管疾病以及病毒系统感染的策略。

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.