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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：
10669199
负责人：
Vernon Bruce Carruthers
金额：
$ 44.27万
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/10669199
关键词：
Acquired Immunodeficiency Syndrome Address Affinity Amino Acids Autophagocytosis Autophagosome Biogenesis Biological Models Cells Cellular biology Chronic Complex Cyst Cytoplasm Development Disease Early identification Eating Eukaryota Event Evolution Eye diseases Genes Goals HIV/AIDS Health Heart Diseases Homeostasis Immune In Vitro Individual Infection Literature Measures Mediating Membrane Mitochondria Molecular Molecular Genetics Mus Ocular Toxoplasmosis Parasites Pathway interactions Patients Persons Play Property Publishing RNA Interference Reactive Oxygen Species Recurrence Respiratory Disease Risk Role Sampling Shapes Structure Testing Tissues Toxoplasma Toxoplasma gondii Toxoplasmosis Vision Work chronic infection defined contribution experience in vivo innovation insight mutant nanobodies nervous system disorder novel organ transplant recipient pathogen postmitotic 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.

慢性弓形虫感染的再激活可引起免疫缺陷个体的眼部、心脏、呼吸道和神经系统疾病。目前的治疗方法不能消除缓慢复制的、持久的弓形虫缓殖子包囊，这些包囊导致再活化和疾病，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，从而消除高危人群中潜在致命性弓形虫脑炎的风险。为了实现这一目标，我们最近已经证明，培养和感染小鼠中的缓殖子包囊的生存能力严重依赖于寄生虫具有基于TgATG 9的靶向破坏的功能性自噬途径。TgATG9缺陷的缓殖子在培养物和实验感染的小鼠中显示出显著减少的自噬和严重的生存能力丧失。由于自噬是细胞稳态所必需的，我们的研究结果支持了一个新的概念，破坏寄生虫的稳态，以平息感染。然而，对弓形虫中的自噬知之甚少，追求这一概念需要识别途径中新的和不同的组分。为了满足这一需求，我们将发现新的自噬途径的早期组件，定义它们如何协同介导自噬结构的发展，并确定它们在体外和体内对寄生虫持久性的贡献。完成拟议的研究将提供概念验证，即靶向寄生虫体内平衡是破坏持久性的有效策略。

项目成果

期刊论文数量（7）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

New and emerging uses of CRISPR/Cas9 to genetically manipulate apicomplexan parasites.

DOI：
10.1017/s003118201800001x
发表时间：
2018-08
期刊：
Parasitology
影响因子：
2.4
作者：
Di Cristina M;Carruthers VB
通讯作者：
Carruthers VB

Structural Features of Apicomplexan Pore-Forming Proteins and Their Roles in Parasite Cell Traversal and Egress.

DOI：
10.3390/toxins9090265
发表时间：
2017-08-29
期刊：
Toxins
影响因子：
4.2
作者：
Guerra AJ;Carruthers VB
通讯作者：
Carruthers VB

Toxoplasma Retromer Is Here to Stay.

DOI：
10.1016/j.pt.2016.05.007
发表时间：
2016-10
期刊：
Trends in parasitology
影响因子：
9.6
作者：
McGovern OL;Carruthers VB
通讯作者：
Carruthers VB

The vacuolar iron transporter mediates iron detoxification in Toxoplasma gondii.

DOI：
10.1038/s41467-023-39436-y
发表时间：
2023-06-20
期刊：
NATURE COMMUNICATIONS
影响因子：
16.6
作者：
Aghabi, Dana;Sloan, Megan;Gill, Grace;Hartmann, Elena;Antipova, Olga;Dou, Zhicheng;Guerra, Alfredo J.;Carruthers, Vern B.;Harding, Clare R.
通讯作者：
Harding, Clare R.

An Uninvited Seat at the Dinner Table: How Apicomplexan Parasites Scavenge Nutrients from the Host.