Morphine and gp120 modulation of Fc gamma mediated macrophage phagocytosis

吗啡和 gp120 对 Fc γ 介导的巨噬细胞吞噬作用的调节

• 批准号: 7901033
• 负责人: Jana Ninkovic
• 金额: $ 1.71万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-20 至 2011-01-19
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7901033
• 关键词: Accounting; Acquired Immunodeficiency Syndrome; Actins; Address; Bacteria; Bacterial Infections; CD4 Positive T Lymphocytes; Cell Line; Cells; Centers for Disease Control and Prevention (U.S.); Charge; Chemosensitization; Chemotaxis; Chronic; Clinical; Communicable Diseases; Comprehension; Cyclic AMP; Data; Disease; Drug usage; Epidemic; Frequencies; Functional disorder; Glycoproteins; Goals; Green Fluorescent Proteins; HIV; HIV Envelope Protein gp120; HIV Infections; HIV Seropositivity; HIV-1; IgG Receptors; Immune Targeting; Immune response; Immune system; Immunity; Immunoglobulin G; Immunologic Deficiency Syndromes; Immunology; Immunosuppression; Impairment; In Vitro; Infection; Injection of therapeutic agent; Lead; Life; Literature; Mediating; Molecular; Morphine; Natural Immunity; Nitrogen; Opiates; Opioid; Patients; Peritoneal Macrophages; Phagocytes; Phagocytosis; Pharmaceutical Preparations; Pharmacology; Play; Population; Process; Production; Quality of life; Reporting; Role; Sepsis; Superoxides; Techniques; Time; Tissues; United States; Virus Diseases; Withdrawal; bactericide; clinical practice; cofactor; design; drug of abuse; env Gene Products; fighting; improved; in vivo; insight; killings; macrophage; neutrophil; new technology; particle; pathogen; polymerization; public health relevance; reactive oxygen intermediate; receptor expression; research study; statistics; trend

DESCRIPTION (provided by applicant): Opiate use and abuse has been known to suppress a number of immune responses and, therefore, have been postulated to serve as cofactor in the progression of HIV-1 infection. According to latest CDC statistics, since the HIV epidemic began, injection drug use has directly and indirectly accounted for more than one-third (36%) of AIDS cases in the United States. The high frequency of bacterial sepsis observed in HIV-positive patients has been shown to be in part due to impairment of innate immunity, specifically macrophage function (chemotaxis, bacterial killing, phagocytosis, and superoxide production). Our goal is to better understand effects of opioids on innate immunity in presence of HIV-1 envelope protein gp120. The specific aims of this proposal will focus on experiments that specifically address mechanisms of morphine and gp120 induced suppression of macrophage's ability to internalize, and eliminate bacterial infections. Macrophage cell lines as well as primary peritoneal macrophages treated in vivo and in vitro will e used to show the effects of chronic morphine and gp120 on this constituent of innate immunity. In aim one, we intend to investigate in vivo and in vitro effects of chronic morphine and gp120 on Fc-gamma receptor (FcgR) mediated phagocytosis of IgG opsonized bacterial particles. We will examine the role of morphine and gp120 in modulation of cAMP, FcgR expression and activation as well as actin polymerization. Additionally in aim two, we propose to study the effects of chronic morphine and gp120 on phago-lysosomal fusion and mechanisms of bacterial killing. Focusing on release of reactive oxygen intermediates (ROIs), reactive nitrogen intermediates (RNIs) and overall bactericidal ability of macrophages. In addition, we will study the effects of gp120 and if and how it modulates morphine induced inhibition of bacterial killing. By performing a detailed analysis of phagocytosis and bactericidal activity in presence of morphine and gp120 we hope to gain insight in general effect of opiates on bacterial clearance by macrophages during HIV infection. PUBLIC HEALTH RELEVANCE: HIV weakens the body's ability to fight disease by targeting immune cells in charge of bacterial clearance. Infections which are rarely seen in those with normal immune systems are deadly to those with HIV. In presence of drugs of abuse such as opioids, this effect is further exacerbated. Mechanisms of interaction between HIV and drugs of abuse have not been well explored. It is important to study the mechanisms of opioid and HIV induced immune suppression so we can design better therapies and improve quality of life.

描述（由申请人提供）：已知阿片类药物的使用和滥用会抑制多种免疫反应，因此被认为是 HIV-1 感染进展中的辅助因子。据美国疾病预防控制中心最新统计，自艾滋病毒流行以来，注射吸毒直接和间接占美国艾滋病病例的三分之一以上（36%）。 HIV 阳性患者中观察到的高频率细菌性脓毒症部分是由于先天免疫受损，特别是巨噬细胞功能（趋化性、细菌杀灭性、吞噬作用和超氧化物产生）。我们的目标是更好地了解阿片类药物在 HIV-1 包膜蛋白 gp120 存在的情况下对先天免疫的影响。 该提案的具体目标将集中于专门解决吗啡和 gp120 诱导的巨噬细胞内化和消除细菌感染能力抑制机制的实验。将使用体内和体外处理的巨噬细胞系以及原代腹膜巨噬细胞来显示慢性吗啡和 gp120 对先天免疫这一组成部分的影响。在目标一中，我们打算研究慢性吗啡和 gp120 对 Fc-gamma 受体 (FcgR) 介导的 IgG 调理细菌颗粒吞噬作用的体内和体外影响。我们将研究吗啡和 gp120 在调节 cAMP、FcgR 表达和激活以及肌动蛋白聚合中的作用。此外，在目标二中，我们建议研究慢性吗啡和 gp120 对吞噬溶酶体融合的影响以及细菌杀灭机制。重点关注活性氧中间体（ROI）、活性氮中间体（RNI）的释放以及巨噬细胞的整体杀菌能力。此外，我们将研究 gp120 的作用以及它是否以及如何调节吗啡诱导的细菌杀灭抑制。通过对吗啡和 gp120 存在下的吞噬作用和杀菌活性进行详细分析，我们希望深入了解阿片类药物对 HIV 感染期间巨噬细胞清除细菌的一般影响。公共卫生相关性：艾滋病毒通过针对负责细菌清除的免疫细胞来削弱人体抵抗疾病的能力。对于免疫系统正常的人来说很少见的感染对于艾滋病毒感染者来说却是致命的。在存在阿片类药物等滥用药物的情况下，这种效应会进一步加剧。艾滋病毒与滥用药物之间相互作用的机制尚未得到很好的探索。研究阿片类药物和艾滋病毒诱导的免疫抑制机制非常重要，这样我们就可以设计更好的疗法并提高生活质量。