Manipulation of host cell acetylome in AIDS opportunistic infection

艾滋病机会性感染中宿主细胞乙酰组的调控

• 批准号: 8604687
• 负责人: William J Sullivan
• 金额: $ 23.4万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-01-15 至 2016-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8604687
• 关键词: AIDS-Related Opportunistic Infections; AIDS/HIV problem; Acetylation; Acetyltransferase; Acquired Immunodeficiency Syndrome; Acute; Address; Adverse effects; Antibodies; Apicomplexa; Area; Bacterial Infections; Benign; Biological; Cells; Central Nervous System Diseases; Cerebral Toxoplasmosis; Cryptosporidium; Cyst; Data; Deacetylase; Development; Environment; Enzymes; Eukaryota; Eukaryotic Cell; Exhibits; Fibroblasts; Folate; Future; Gene Expression; Genes; Global Change; HIV; Highly Active Antiretroviral Therapy; Histones; Human; Immune; Immunoblotting; Individual; Infection; Lead; Life; Lysine; Maps; Modification; Opportunistic Infections; Parasites; Pathogenesis; Pathology; Pathway interactions; Patients; Peptides; Pharmaceutical Preparations; Phosphorylation; Population; Post-Translational Protein Processing; Protein Acetylation; Proteins; Proteome; Quality of life; RNA Interference; Research; Role; Staging; System; Therapeutic Intervention; Tissue-Specific Gene Expression; Toxoplasma; Toxoplasma gondii; Toxoplasmosis; Transcript; Viral; Virulence; base; combat; effective therapy; innovation; insight; mortality; pathogen; penis foreskin; protein expression; public health relevance; research study; response; transcription factor; treatment strategy

DESCRIPTION (provided by applicant): Opportunistic pathogens remain a significant problem in HIV/AIDS patients, decreasing the quality of life and often posing life-threatening acute infection. Toxoplasma gondii is an obligate intracellular protozoan parasite (phylum Apicomplexa) that has permanently infected up to 1/3 of the world's population. While generally considered benign in immune-competent individuals, Toxoplasma is notorious for recrudescing into active infection in AIDS patients. The frontline treatment of anti-folates exhibits pronounced adverse effects and a sulfa component that allergenic patients cannot tolerate. Thus, an urgent need exists to develop safer and more effective therapies to treat AIDS-toxoplasmosis. Like other intracellular AIDS opportunistic infections, Toxoplasma radically alters its host cell environment to suit the parasite's needs. An innovative treatment strategy is to interfere with the modifications made to the host cell, thereby making it inhospitable for parasite replication and development. Unfortunately, a deficiency in our understanding of host-pathogen interactions has stymied the development of new drugs. It has recently been found that intracellular viral and bacterial pathogens alter acetylation of host cell proteins, manipulating a major cellular signalin network in favor of parasite survival. We hypothesize that Toxoplasma also manipulates host cell acetylation and present evidence in support of this idea. We show that Toxoplasma infection induces alterations in the transcript levels of enzymes modulating protein acetylation. Furthermore, immunoblotting with anti-acetyl- lysine reveals global changes in protein acetylation levels in infected host cells. We therefore propose to determine the host cell proteins modified by Toxoplasma infection in the context of virulence and development into its latent stage, and identify specific lysine (de)acetylation enzymes that are relevant to infection. Given the scope of lysine acetylation found in eukaryotic cells and the common theme of multiple intracellular pathogens disrupting acetylation dynamics, our findings promise to have far-reaching impact on other medically relevant infections, including HIV itself and other AIDS opportunist pathogens such as Cryptosporidium.

描述（由申请人提供）：机会性病原体仍然是艾滋病毒/艾滋病患者的一个重大问题，降低了生活质量，并常常造成危及生命的急性感染。弓形虫是一种专性细胞内原生动物寄生虫（顶复门），已永久感染世界上多达 1/3 的人口。虽然弓形虫通常被认为在免疫能力强的个体中是良性的，但它因在艾滋病患者中复发为活动性感染而臭名昭著。抗叶酸药物的一线治疗效果显着 不良反应和过敏患者无法耐受的磺胺成分。因此，迫切需要开发更安全和更有效的疗法来治疗艾滋病弓形虫病。与其他细胞内艾滋病机会性感染一样，弓形虫从根本上改变其宿主细胞环境以适应寄生虫的需要。一种创新的治疗策略是干扰 对宿主细胞进行修改，从而使其不适合寄生虫的复制和发育。不幸的是，我们对宿主与病原体相互作用的理解不足阻碍了新药的开发。最近发现，细胞内病毒和细菌病原体会改变宿主细胞蛋白质的乙酰化，操纵主要的细胞信号网络有利于寄生虫的生存。我们假设弓形虫也操纵宿主细胞乙酰化，并提供证据支持这一想法。我们发现弓形虫感染会引起调节蛋白质乙酰化的酶转录水平的改变。此外，抗乙酰赖氨酸的免疫印迹揭示了受感染宿主细胞中蛋白质乙酰化水平的整体变化。因此，我们建议确定宿主细胞蛋白 弓形虫感染在毒力和发展到潜伏阶段的背景下进行修饰，并鉴定与感染相关的特定赖氨酸（去）乙酰化酶。鉴于真核细胞中赖氨酸乙酰化的范围以及破坏乙酰化动力学的多种细胞内病原体的共同主题，我们的研究结果有望对其他医学相关感染产生深远的影响，包括艾滋病毒本身和其他艾滋病机会病原体，例如隐孢子虫。