Identifying The Machinery That Translocates Toxoplasma Effectors Into The Host Cell

识别将弓形虫效应器转移到宿主细胞中的机制

基本信息

批准号：
9761426
负责人：
John C Boothroyd
金额：
$ 54.53万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-09 至 2022-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9761426
关键词：
AIDS/HIV problem Acquired Immunodeficiency Syndrome Acute Adult Animals Apicomplexa Attenuated Binding Biochemical Genetics Biological Biology Bone Marrow Cells Cellular biology Chronic Complement Complex Cryptosporidium Cryptosporidium parvum Cyst Cytoplasmic Granules Cytosol DHFR gene Disease Dissection Epithelial Cells Epitopes Fetal Development Foundations Future Genetic Screening Goals Growth HIV Human Immune Immune response Immunocompromised Host Individual Infection Infectious Agent Intestines Knock-in Knock-out Knowledge Libraries Lymphoma Malaria Malignant Neoplasms Mass Spectrum Analysis Medical Membrane Mus New Territories Oncogenes Oncoproteins Organ Transplantation Parasites Pathogenesis Pathogenicity Patients Pharmaceutical Preparations Phase Phenotype Plasmodium Play Process Protein Export Pathway Protein Kinase Proteins Pyrimethamine Reporter Reporting Role Sterility Sulfadiazine System Testing Therapeutic Intervention Time Toxoplasma Toxoplasma gondii Transplantation Up-Regulation Vaccines Vacuole Virulence Work asexual base c-myc Genes diarrheal disease genetic approach genome sequencing in vivo innovation interest knock-down macrophage mouse model mutant nervous system disorder novel oral infection pathogen phosphoproteomics rhoptry screening transcriptomics treatment strategy

项目摘要

Abstract The major pathogenic species of Apicomplexa are all intracellular eukaryotic parasites that generally reproduce within a parasitophorous vacuole (PV) in infected host cells. This niche presents both an opportunity and a challenge to the parasites growing within – on the one hand, they are sequestered from some of the immune defenses that might detect their presence but at the same time, the PV membrane (PVM) presents a physical barrier to the export of protein effectors necessary to modulate host functions to the parasite's advantage. The phylum Apicomplexa includes many important human and animal pathogens including Plasmodium sp., the cause of human malaria, Cryptosporidium parvum, the cause of debilitating diarrheal disease, and Toxoplasma gondii, the cause of serious neurologic disease in the developing fetus and those who are immunocompromised through cancer (e.g., lymphoma), transplantation or infections, such as HIV-AIDS. We have recently determined that Toxoplasma tachyzoites have the ability to dramatically and specifically up-regulate expression of the human oncogene, c-Myc, using an effector released from dense granules, called GRA16. Using a genetic screen for mutants defective in c-Myc up-regulation, we have also recently identified the first components of the Toxoplasma machinery that translocates GRA16 and other dense granule effectors across the PVM. These novel proteins have been dubbed MYR1, MYR2 and MYR3. The goal of the work proposed here is to identify the complete or near complete machinery involved in translocation of effectors across the PVM, determine the host responses that are dependent on this machinery, and elucidate the importance of these effectors in Toxoplasma pathogenesis. We will do this through using a combination of biochemical and genetic approaches. Through this work, we will both unveil an important and novel piece of cell biology and identify crucial parasite components for eventual chemotherapeutic targeting and amelioration of the disease caused by this and related parasites.

抽象的 Apicomplexa的主要致病性物种都是细胞内真核生物通常在受感染宿主的寄生虫液泡（PV）内繁殖的寄生虫细胞。这种利基既给寄生虫都带来了机会，也是一个挑战在内部 - 一方面，它们是从某些免疫防御措施中隔离的可能检测到它们的存在，但同时，PV膜（PVM）呈现A 将蛋白质效应导出的物理障碍将宿主功能调节至寄生虫的优势。门apicomplexa包括许多重要的人类和动物病原体包括疟原虫，是人类疟疾的原因，隐孢子虫parvum，导致腹泻病的原因和弓形虫的原因，这是严重的原因发育中的胎儿中的神经疾病和那些免疫受损的人通过癌症（例如淋巴瘤），移植或感染，例如HIV-AID。我们最近确定毒品tachyzoites具有显着的能力并特别上调了使用效应器的人类癌基因C-MYC的表达从致密颗粒中释放，称为Gra16。使用突变体的遗传屏幕 C-MYC上调有缺陷，我们最近还确定了第一部分易位的GRA16和其他致密颗粒效果的弓形虫机械跨PVM。这些新颖的蛋白质被称为MYR1，MYR2和MYR3。这这里提出的工作的目标是确定完整或接近完整的涉及跨PVM效应易位的机械，确定依赖此机械的主机响应，并阐明这些作用在弓形虫发病机理中的重要性。我们将通过结合生化方法和遗传方法。通过这项工作，我们将揭露一个重要而新颖的细胞生物学并确定最终化学治疗靶向的关键寄生虫成分并改善该疾病是由这种疾病和相关寄生虫引起的。