Analysis of the macrophage membrane proteome: effects of viral infection

巨噬细胞膜蛋白质组分析：病毒感染的影响

• 批准号: 8969989
• 负责人: VERONICA SANCHEZ
• 金额: $ 7.35万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-05-19 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8969989
• 关键词: ATP binding cassette transporter 1; Acquired Immunodeficiency Syndrome; Acute; Adult; Affect; Age; Antiviral Response; Apoptosis; Bacterial Infections; Binding; Biology; CD36 gene; Cardiovascular Diseases; Cell membrane; Cell physiology; Cell surface; Cells; Cellular Stress; Cholesterol; Chronic; Congenital Abnormality; Cytomegalovirus; Cytomegalovirus Infections; Cytoplasm; Disease; Epidermal Growth Factor Receptor; Fc Receptor; Foam Cells; Foundations; Future; Genes; Global Change; Goals; Growth Factor Receptors; HIV; HIV Budding; Herpesviridae; Human; Immunocompromised Host; Infection; Inflammation; Inflammatory; Influenza; Interferons; Investigation; LOX gene; Lipids; Lipoprotein Binding; Lipoproteins; Malignant Neoplasms; Mass Spectrum Analysis; Measures; Mediating; Membrane; Membrane Fluidity; Membrane Lipids; Membrane Microdomains; Membrane Protein Traffic; Metabolism; Mus; Mycoses; Myeloid Cells; Organ Transplantation; PDGFRB gene; Pathology; Pathway interactions; Patients; Pattern recognition receptor; Phagocytosis; Phase; Process; Proteins; Proteome; Regulation; Reporting; Risk; Role; SR-BI receptor; Signal Transduction; Sphingolipids; Stress; Surface; Transplant Recipients; Viral; Virion; Virus; Virus Diseases; Work; cholesterol transporters; latent infection; lipid metabolism; lipid transport; macrophage; microbial; monocyte; oxidized low density lipoprotein; pathogen; public health relevance; receptor; receptor function; research study; response; scavenger receptor; uptake; viperin

 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.

 描述（由申请人提供）：HCMV 是 β-疱疹病毒，并在受感染宿主的一生中作为持续感染而维持。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患者。该病毒无处不在，大多数成年人在 40 岁之前就被感染。在健康宿主中，感染的急性期是自限性的，病毒会建立潜伏感染，从而导致感染。 响应各种细胞应激而重新激活。骨髓谱系细胞是病毒的储存库。 HCMV感染诱发慢性炎症；因此，HCMV持久性在心血管疾病和癌症等具有炎症成分的疾病的病理学中的作用是许多研究的焦点。 HCMV 在受感染细胞的细胞质中获得脂质包膜，但人们对感染对脂质代谢和运输的影响知之甚少。我们之前已经表明，感染会阻止 THP-1 衍生的巨噬细胞转化为负载脂质的泡沫细胞，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，脂蛋白是一种 由细胞表面的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区，从而抑制清道夫受体功能。该项目的最终目标是了解控制 HCMV 感染细胞中脂筏稳定性和清道夫受体功能的机制。为了实现这一目标，我们将研究感染后质膜组成的变化，并确定 viperin、ABCA1 和 SR-BI 通过影响脂筏稳定性来调节受体活性的作用。目前的研究将为未来的工作奠定基础。