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Identifying novel players in Toxoplasma autophagy during chronic infection”

识别慢性感染期间弓形虫自噬的新参与者 –

基本信息

批准号：
10372165
负责人：
Vernon Bruce Carruthers
金额：
$ 23.4万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-03-15 至 2023-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10372165
关键词：
Acquired Immunodeficiency Syndrome Automobile Driving Autophagocytosis Biological Assay Birth Blindness Brain CRISPR/Cas technology Cells Cellular biology Chemicals Chronic Code Cyst Defect Disease Eating Eye Genes Genetic Screening Goals Health Heart Homeostasis Human Immune Immune system Individual Infant Infection Intervention Investigation Life Literature Lung Measures Mitotic Molecular Genetics Mus Mutagenesis Mutation Ocular Toxoplasmosis Organ Organ Transplantation Parasites Pathway interactions Phase Phenotype Populations at Risk Pregnancy Property Proteins Publishing Reporter Risk Role Seeds Single Nucleotide Polymorphism Site-Directed Mutagenesis Testing Time Tissues Toxoplasma Toxoplasma gondii Toxoplasmosis Vision Work acute infection base cancer therapy chronic infection defined contribution experience genome sequencing in vivo mouse model mutant novel operation prime editing protein degradation spatiotemporal transplantation therapy whole genome

项目摘要

The protozoan parasite Toxoplasma gondii renders nearly one third of the global human population at risk of experiencing disease due to reactivation of chronic infection. Current treatments fail to eliminate the slow replicating, persistent Toxoplasma bradyzoite cysts that seed reactivation and ensuing disease in the eyes, brain, heart or lungs. Individuals with ocular toxoplasmosis are particularly at risk of experiencing progressive loss of vision due to sequential periods of reactivation. Our long-term goal is to identify critical liabilities for disrupting Toxoplasma persistence, thereby precluding reactivated disease in at risk individuals. Toward this goal, we have recently demonstrated that the viability of bradyzoite cysts in culture and in infected mice relies on the parasite having a functional autophagy pathway. However, little is known about autophagy in Toxoplasma and exploiting parasite autophagy to impact infection requires identifying new and divergent components in the pathway. To meet this need, leveraging our recent genetic screen we will identify novel components of the autophagy pathway by developing for the first time in T. gondii a “prime editing” approach for pooled identification of phenotype driving single nucleotide variants, define the general roles of novel components in parasite autophagy, and measure their impact on acute and chronic infection. Completing the proposed studies is expected to identify at least 4 new and divergent components of T. gondii autophagy that can be prioritized for deeper analysis and open novel avenues of investigation in the next phase of this work.

原生动物寄生虫弓形虫（Toxoplasma gondii）使全球近三分之一的人口面临感染的风险。由于慢性感染的重新激活而经历疾病。目前的治疗方法无法消除缓慢复制，持续存在的弓形虫缓殖子包囊，在眼、脑、心脏或肺患有眼弓形虫病的个体特别有经历进行性视力丧失的风险，重新激活的连续时期。我们的长期目标是确定破坏弓形虫的关键责任持久性，从而防止在风险个体中重新激活疾病。为了实现这一目标，我们最近证明了缓殖子包囊在培养物和感染小鼠中的生存能力依赖于具有功能性自噬途径然而，对弓形虫和寄生虫的自噬知之甚少自噬影响感染需要识别途径中新的和不同的组分。为了满足这一需求，利用我们最近的遗传筛选，我们将通过开发第一次在T。弓形虫“引物编辑”方法用于合并鉴定表型驱动的单核苷酸变体，定义寄生虫自噬中新成分的一般作用，并测量其对急性慢性感染。完成拟议的研究，预计将确定至少4个新的和不同的组成T.弓形虫自噬可以优先进行更深入的分析，并开辟新的途径，在这项工作的下一阶段进行调查。