Cytoskeletal machinery driving invasion by the human pathogen, Toxoplasma gondii.

细胞骨架机制驱动人类病原体弓形虫的入侵。

• 批准号: 10322763
• 负责人: Ke Hu
• 金额: $ 40.08万
• 依托单位: ARIZONA STATE UNIVERSITY-TEMPE CAMPUS
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10322763
• 关键词: Actomyosin; Antiparasitic Agents; Apical; Apicomplexa; Automobile Driving; Biochemical; Biophysics; Blindness; Calcium; Cells; Complex; Cytoskeletal Proteins; Defect; Development; Drug Targeting; Evolution; Fetus; Goals; Hand; Higher Order Chromatin Structure; Human; Image; Immunocompromised Host; Impairment; In Vitro; Individual; Infection; Invaded; Lead; Left; Link; Mechanics; Membrane; Methodology; Microtubules; Modeling; Molecular; Motor; Neurologic; Ocular Toxoplasmosis; Opportunistic Infections; Organelles; Orthologous Gene; Parasites; Persons; Planet Earth; Plant Roots; Polymers; Protein Secretion; Proteins; Regulation; Retina; Role; Structure; Testing; Toxoplasma gondii; Toxoplasmosis; Tubulin; Variant; Work; cell cortex; cell motility; gene discovery; human pathogen; in vivo; mutant; novel; obligate intracellular parasite; parasite invasion; prevent; toxoplasmic encephalitis

Project Summary: Approximately 20% of the people on Earth are permanently infected with the unicellular parasite, Toxoplasma gondii. T. gondii is one of the leading causes of congenital neurological defects in humans, and an agent for devastating opportunistic infections in immunocompromised individuals. Ocular toxoplasmosis is one of the most common retinal infections and can lead to blindness. As an obligate intracellular parasite, T. gondii must first invade cells of its host in order to replicate. In the preliminary study, we found that the disruption of an iconic structure in T. gondii, the conoid, is linked to drastically impaired invasion. This is an aspect of invasion that has not been explored, as previous work on invasion has mainly centered on the regulation and activity of the actomyosin motor complex and protein secretion from specialized membrane-bound organelles. To explore this new direction, we propose two complementary aims to (a) determine the function of the conoid in host cell invasion (Aim 1), and (b) elucidate how this novel cytoskeletal complex is constructed (Aim 2). Using the mutants we have generated, Aim 1 will determine whether the conoid facilitates invasion by secretion, motility, directly assisting the physical interaction between the parasite and the host cell during attachment, or overcoming the cortical tension of the host cell. Aim 2 will identify and characterize structural determinants of the conoid by integrating gene discovery with structural and functional analyses. We will combine state of the art imaging, biophysical, biochemical, and evolutionary approaches. This comprehensive strategy will greatly enhance our ability to identify novel components in this unique structure as drug targets.

项目概要： 地球上大约 20% 的人永久感染这种单细胞寄生虫， 弓形虫。弓形虫是先天性神经缺陷的主要原因之一 人类，以及对免疫功能低下的个体造成毁灭性机会性感染的药剂。 眼弓形虫病是最常见的视网膜感染之一，可导致失明。作为一个 作为专性细胞内寄生虫，弓形虫必须首先侵入宿主细胞才能复制。在 初步研究，我们发现弓形虫标志性结构（锥体）的破坏与 侵袭力严重受损。这是入侵的一个方面，之前还没有被探索过 关于入侵的工作主要集中在肌动球蛋白运动复合体的调节和活性上 以及专门的膜结合细胞器的蛋白质分泌。为了探索这个新方向，我们 提出两个互补的目标（a）确定圆锥体在宿主细胞侵袭中的功能（Aim 1) 和 (b) 阐明这种新型细胞骨架复合物是如何构建的（目标 2）。使用突变体我们 已经生成，目标 1 将确定锥状体是否通过分泌、运动、 在附着过程中直接协助寄生虫和宿主细胞之间的物理相互作用，或 克服宿主细胞的皮质张力。目标 2 将识别和表征结构 通过将基因发现与结构和功能分析相结合来确定圆锥形的决定因素。我们 将结合最先进的成像、生物物理、生物化学和进化方法。这 全面的策略将大大增强我们在这个独特的领域识别新成分的能力 结构作为药物靶标。

项目成果

The cortical microtubules of Toxoplasma gondii underlie the helicity of parasite movement.

弓形虫的皮质微管是寄生虫运动螺旋性的基础。

• DOI: 10.1242/jcs.261270
• 发表时间: 2023
• 期刊: Journal of cell science
• 影响因子: 4
• 作者: Tengganu,IsadonnaF;AriasPadilla,LuisaF;MuneraLopez,Jonathan;Liu,Jun;Brown,PeterT;Murray,JohnM;Hu,Ke
• 通讯作者: Hu,Ke

An apical protein, Pcr2, is required for persistent movement by the human parasite Toxoplasma gondii.

• DOI: 10.1371/journal.ppat.1010776
• 发表时间: 2022-08
• 期刊: PLoS pathogens
• 影响因子: 6.7