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的主要致病菌种均为细胞内真核生物通常在受感染宿主体内的寄生液泡 (PV) 内繁殖的寄生虫这个生态位对寄生虫的生长既是机遇也是挑战。一方面，它们与一些免疫防御隔离，可能会检测到它们的存在，但同时，PV 膜 (PVM) 会呈现出调节宿主功能所需的蛋白质效应子输出的物理障碍寄生虫的优势。顶复门包括许多重要的人类和动物病原体包括引起人类疟疾的疟原虫 (Plasmodium sp.)、小隐孢子虫 (Cryptosporidium parvum) 导致衰弱性腹泻病的原因，而弓形虫则是导致严重腹泻的原因发育中胎儿和免疫功能低下者的神经系统疾病通过癌症（例如淋巴瘤）、移植或感染（例如艾滋病毒/艾滋病）。最近确定弓形虫速殖子具有显着并使用效应器特异性上调人类癌基因 c-Myc 的表达使用突变体基因筛选从致密颗粒中释放出来，称为 GRA16。 c-Myc 上调有缺陷，我们最近还确定了第一个组件易位 GRA16 和其他致密颗粒效应器的弓形虫机器这些新蛋白质被称为 MYR1、MYR2 和 MYR3。这里提出的工作目标是确定完整或接近完整的参与跨 PVM 效应器易位的机械，确定依赖于该机制的宿主反应，并阐明我们将通过这些效应器在弓形虫发病机制中的重要性来做到这一点。结合使用生化和遗传学方法。通过这项工作，我们将揭开一种重要而新颖的细胞的面纱生物学并确定最终化疗靶向的关键寄生虫成分以及改善由这种寄生虫和相关寄生虫引起的疾病。