Role of c-Myc up-regulation in Toxoplasma infection

c-Myc 上调在弓形虫感染中的作用

基本信息

批准号：
8845424
负责人：
John C Boothroyd
金额：
$ 23.73万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-12-01 至 2016-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8845424
关键词：
AIDS-Related Opportunistic Infections Acetylation Acquired Immunodeficiency Syndrome Affect Animals Anti-Retroviral Agents Antibodies Automobile Driving Binding Biological Biology Blood CMV promoter Candidate Disease Gene Cell Line Cells Chronic Code Country Cyst Disease Embryo Encephalitis Ethylnitrosourea Eukaryota Foundations Future Gene Expression Gene Expression Profile Genes Genetic Genetic Screening Genomic DNA Goals Growth HIV diagnosis Health Human Image Immune Immune response Immunoprecipitation In Vitro Incidence Infection Infection Control Investigation Knock-out Lead Learning Life Luciferases Mass Spectrum Analysis Mediating Medical Molecular Molecular Genetics Monitor Mus Mutation Neospora Neospora caninum New Territories Opportunistic Infections Parasites Pathogenesis Patients Pharmaceutical Preparations Phenotype Phosphorylation Population Post-Translational Protein Processing Process Proteins Pyrimethamine Regulation Relative (related person)Reporter Role Site Sorting - Cell Movement Source Sterility Sulfadiazine Technology Testing Therapeutic Intervention Toxoplasma Toxoplasma gondii Up-Regulation Virulence Work base c-myc Genes co-infection fitness gene function in vivo interest intraperitoneal mutant novel novel strategies pathogen promoter public health relevance research study tool trait transcription factor transcriptome sequencing treatment strategy

项目摘要

DESCRIPTION (provided by applicant): Toxoplasma is a ubiquitous pathogen that infects and reproduces in virtually any nucleated cell of warm- blooded animals. This single-celled eukaryote is of great medical importance not least because infections in AIDS patients can lead to life-threatening illness. While use of anti-retroviral treatments (ART) has reduced the incidence of Toxoplasmic encephalitis (TE) in western countries with access to the therapy, it remains a significant AIDS-related opportunistic infection among people with late HIV diagnosis or without access to ART. Our results show that a key host regulator, c-Myc, is induced in human cells infected by Toxoplasma. Importantly, the increase of c-Myc is not a result of a nonspecific host immune response, as the closely related intracellular parasite, Neospora caninum, does not elicit this phenotype. Furthermore, a coinfection of cells with both Toxoplasma and Neospora results in an increase in host c-Myc showing that c-Myc is actively upregulated by Toxoplasma (rather than repressed by Neospora). Here, we propose a novel approach that employs genetic tools for Toxoplasma, developed in this and other labs, with cutting-edge technologies developed in the c-Myc field to examine the mechanism and role of c-Myc regulation during Toxoplasma infection. This study will test the hypothesis that the activation of c-Myc in Toxoplasma-infected host cells is mediated by specific Toxoplasma gene(s). Forward genetic screens have already yielded a candidate gene for this effect and mutants in this gene will be used to uncover the mechanism underlying c-Myc induction as well as the role of c-Myc induction in the context of Toxoplasma infection. The results of this study will reveal valuable information about Toxoplasma's interaction with its host and make possible future investigation aimed at interfering with c-Myc induction as a novel treatment for the infection.

描述（由申请人提供）：弓形虫是一种普遍存在的病原体，几乎可以在温血动物的任何有核细胞中感染和繁殖，这种单细胞真核生物具有重要的医学意义，尤其是因为艾滋病患者的感染可能导致危及生命的疾病。逆转录病毒治疗（ART）降低了西方国家弓形虫脑炎（TE）的发病率，但它仍然是一种与艾滋病相关的重要机会性感染我们的研究结果表明，弓形虫感染的人类细胞中会诱导关键的宿主调节因子 c-Myc，重要的是，c-Myc 的增加并不是非特异性宿主的结果。免疫反应，作为密切相关的细胞内寄生虫，新孢子虫，不会引起这种表型。此外，细胞与弓形虫和新孢子虫的共感染会导致宿主 c-Myc 的增加，表明 c-Myc。被弓形虫主动上调（而不是被新孢子虫抑制）。在这里，我们提出了一种新方法，采用本实验室和其他实验室开发的弓形虫遗传工具，并采用 c-Myc 领域开发的尖端技术来检查其机制。弓形虫感染期间 c-Myc 调节的作用本研究将检验弓形虫感染宿主细胞中 c-Myc 的激活是由特定弓形虫介导的假设。正向遗传筛选已经产生了这种效应的候选基因，该基因的突变体将用于揭示 c-Myc 诱导的机制以及 c-Myc 诱导在弓形虫感染中的作用。这项研究的结果将揭示有关弓形虫与其宿主相互作用的有价值的信息。并使未来的研究成为可能，旨在干扰 c-Myc 诱导作为感染的新型治疗方法。