Analysis of the macrophage membrane proteome: effects of viral infection

 描述（由申请方提供）：HCMV是β-疱疹病毒，在受感染宿主的一生中作为持续感染维持。从历史上看，这种病毒的感染对免疫功能低下的人构成威胁，包括艾滋病患者和接受器官移植的人。该病毒无处不在，大多数成年人在40岁之前感染。在健康宿主中，感染的急性期是自限性的，病毒建立潜伏感染， 在应对各种细胞应激时被重新激活。髓系细胞是病毒的储存库。HCMV感染诱导慢性炎症;因此，HCMV持续性在具有炎症组分的疾病（例如心血管疾病和癌症）的病理学中的作用是许多研究的焦点。HCMV在感染细胞的细胞质中获得脂质包膜，但关于感染对脂质代谢和运输的影响知之甚少。我们以前已经表明，感染阻断了THP-1衍生的巨噬细胞转化为脂质负载的泡沫细胞，以响应氧化LDL的治疗。随后，我们观察到病毒抑制了细胞结合脂蛋白的能力， 细胞表面清道夫受体介导的相互作用。我们的研究表明，感染可能会破坏质膜上的脂筏微结构域，从而抑制清道夫受体功能。本项目的最终目标是了解HCMV感染细胞中控制脂筏稳定性和清道夫受体功能的机制。为了实现这一目标，我们将调查感染后质膜组成的变化，并确定蝰蛇蛋白，ABCA 1，和SR-BI的受体活性的调节作用，通过其对脂筏稳定性的影响。本研究为今后的工作奠定了基础。

 DESCRIPTION (provided by applicant): HCMV is beta-herpesvirus and is maintained for the lifetime of the infected host as a persistent infection. Historically, infection with this virus poes a threat to the immunocompromised, including patients with AIDS and those receiving organ transplants. The virus is ubiquitous and most adults are infected by age 40. In the healthy host, the acute phase of infection is self-limiting and the virus establishes a latent infection that can be reactivated in response to a variety of cellular stresses. Cells of the myeloid lineage are the reservoir for the virus. HCMV infection induces chronic inflammation; thus, the role of HCMV persistence in the pathology of diseases with inflammatory components, such as cardiovascular disease and cancer, is the focus of many studies. HCMV acquires a lipid envelope in the cytoplasm of infected cells but little is known about the effects of infection on lipid metabolism and trafficking. We have previously shown that infection blocked the conversion of THP-1 derived macrophages into lipid-laden foam cells in response to treatment with oxidized LDL. Subsequently, we observed that the virus inhibited the ability of cells to bind the lipoprotein, an interaction mediated by scavenger receptors on the cell surface. Our studies indicate that infection likely disrupts lipid raft microdomains on the plasma membrane and thereby inhibits scavenger receptor functions. The ultimate goal of this project is to understand the mechanisms that control lipid raft stability and scavenger receptor function in HCMV- infected cells. To accomplish this goal we will investigate changes in plasma membrane composition after infection and determine the roles of viperin, ABCA1, and SR-BI in regulation of receptor activity through their effects on lipid raft stability. The present studies will provide the foundation for future work.