Parasite autophagy as a key survival mechanism for the AIDS-associated pathogen Toxoplasma gondii

寄生虫自噬是艾滋病相关病原体弓形虫的关键生存机制

基本信息

批准号：
10296195
负责人：
Vernon Bruce Carruthers
金额：
$ 45.65万
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：
2015
资助国家：
美国
起止时间：
2015-12-01 至 2026-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10296195
关键词：
AIDS/HIV problem Acquired Immunodeficiency Syndrome Address Affinity Amino Acids Autophagocytosis Autophagosome Biogenesis Biological Models Cells Cellular biology Chronic Complex Cyst Development Disease Eating Eukaryota Event Evolution Genes Goals Health Heart Diseases Homeostasis Immune In Vitro Individual Infection Literature Lung diseases Measures Mediating Membrane Mitochondria Mitotic Molecular Molecular Genetics Mus Ocular Toxoplasmosis Organ Transplantation Parasites Pathway interactions Patients Play Property Publishing RNA Interference Reactive Oxygen Species Recurrence Risk Role Sampling Seeds Structure Testing Tissues Toxoplasma Toxoplasma gondii Toxoplasmosis Transplant Recipients Vision Work base chronic infection defined contribution experience in vivo innovation insight mutant nanobodies nervous system disorder novel pathogen prevent recruit spatiotemporal toxoplasmic encephalitis virtual

项目摘要

Reactivation of chronic Toxoplasma gondii infection causes ocular, cardiac, respiratory, and neurologic disease in immune-deficient individuals. Current treatments fail to eliminate the slow replicating, persistent Toxoplasma bradyzoite cysts that seed reactivation and disease, which manifests most severely as Toxoplasmic encephalitis. Our long-term goal is to identify critical liabilities for disrupting Toxoplasma persistence, thereby eliminating the risk of potentially fatal Toxoplasmic encephalitis in at-risk individuals. Toward this goal, we have recently demonstrated that the viability of bradyzoite cysts in culture and in infected mice critically relies on the parasite having a functional autophagy pathway based on targeted disruption of TgATG9. TgATG9 deficient bradyzoites show markedly reduced autophagy and severe loss of viability in culture and in experimentally infected mice. Since autophagy is necessary for cellular homeostasis, our findings support a new concept of disrupting parasite homeostasis to quell infection. However, little is known about autophagy in Toxoplasma and pursuing this concept requires identifying new and divergent components in the pathway. To meet this need, we will discover novel early components of the autophagy pathway, define how they cooperatively mediate the development of autophagic structures, and determine their contributions to parasite persistence in vitro and in vivo. Completing the proposed studies will provide proof-of-concept that targeting parasite homeostasis is an effective strategy to disrupt persistence.

慢性弓形虫感染的重新激活会导致免疫缺陷个体出现眼部、心脏、呼吸系统和神经系统疾病。目前的治疗方法无法消除复制缓慢、持续存在的弓形虫缓殖子包囊，这些包囊会导致重新激活和疾病，最严重的表现为弓形虫脑炎。我们的长期目标是确定破坏弓形虫持久性的关键责任，从而消除高危人群患潜在致命弓形虫脑炎的风险。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受感染小鼠中的生存能力严重依赖于具有基于 TgATG9 靶向破坏的功能性自噬途径的寄生虫。 TgATG9 缺陷的缓殖子在培养物和实验感染的小鼠中表现出明显减少的自噬和严重的活力丧失。由于自噬对于细胞稳态是必要的，因此我们的研究结果支持了破坏寄生虫稳态以平息感染的新概念。然而，人们对弓形虫中的自噬知之甚少，追求这一概念需要识别该途径中新的和不同的成分。为了满足这一需求，我们将发现自噬途径的新型早期成分，定义它们如何协同介导自噬结构的发育，并确定它们对体外和体内寄生虫持久性的贡献。完成拟议的研究将提供概念验证，即针对寄生虫体内平衡是破坏持久性的有效策略。