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"Biting" of human cells by Entamoeba histolytica: a novel cytotoxic mechanism

溶组织内阿米巴“咬”人体细胞：一种新的细胞毒性机制

基本信息

批准号：
8618558
负责人：
Katherine S Ralston
金额：
$ 16.2万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-12-01 至 2016-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8618558
关键词：
Address Amebic colitis Amoeba genus Area Biological Biological Assay Bite Calcium Cell Communication Cell Death Cell Line Cells Cellular biology Cessation of life Child Mortality Data Defect Disease Dose Drug Targeting Eating Entamoeba histolytica Epithelial Cells Extramural Activities Flow Cytometry Funding Genes Genetic Genetic Screening Greek Human Human Bites Image Immune Infection Ingestion Intestines Invaded Investigation K22 Award Kinetics Knowledge Laboratories Life Measures Membrane Microscopy Molecular Morbidity - disease rate Mus Names Nature Parasites Parasitic Diseases Parasitic infection Pathogenesis Pathology Pathway interactions Principal Investigator Proteins Publications Role Signal Transduction Source Tissues Toxin Vaccine Therapy Virulence Virulence Factors Work base cell killing collaborative environment cytotoxic design experience fighting in vivo inhibitor/antagonist innovation insight killings mutant new technology novel novel strategies novel therapeutics pathogen porin prevent protozoan amoebapore proteins tool

项目摘要

I propose to study the pathogenesis of amoebic colitis, a global parasitic infection and a major source of morbidity and mortality of children. Entamoeba histolytica was named "histolytica" for its destruction of host tissues and invasion of the intestine, but the mechanism was unknown. I recently made the surprising discovery that amoebae kill by biting off and ingesting distinct pieces of living human cells, resulting in intracellular calcium elevation and eventual death. I named this "trogocytosis-like ingestion" (Greek, trogo-: nibble) due to similarity to trogocytosis in immune cells. I hypothesize that pathology in amoebic colitis results from parasites invading the intestine by nibbling the epithelial cells that line the gut. It is likely that the novel killing mechanism requires unique phagocytic machinery and that the components represent new drug targets. Therefore, I propose to uncover the signaling mechanisms underlying trogocytosis-like ingestion. Furthermore, I propose to re-examine the long-standing hypothesis that the E. histolytica pore-forming proteins, known as the "amoebapores," are secreted cytotoxic effectors. Successful completion of this work will create a paradigm shift in the function of the amoebapores, and will also allow us to identify novel virulence factors, ultimately allowing us to define the basic mechanism of disease.

我建议研究阿米巴结肠炎的发病机制，阿米巴结肠炎是一种全球性的寄生虫感染，也是结肠炎的主要来源。儿童发病率和死亡率。溶组织内阿米巴因其对宿主的破坏作用而得名组织和肠的侵袭，但机制尚不清楚。我最近做了一个令人惊讶的发现变形虫通过咬下并吞噬不同的人体活细胞碎片来杀人，细胞内钙升高并最终死亡。我把这种现象命名为“类胞裂症”（希腊语，trogo-：蚕食），这是由于与免疫细胞中的胞啃作用相似。我假设阿米巴结肠炎的病理学寄生虫通过啃食肠道上皮细胞侵入肠道。很可能这部小说杀伤机制需要独特的吞噬机制，并且这些成分代表了新的药物靶点。因此，我建议揭示的信号转导机制，类似的摄入。此外，委员会认为，我建议重新检查长期存在的假设，即E。溶组织孔形成蛋白，称为 “变形虫”是分泌的细胞毒性效应物。这项工作的成功完成将创造一个范例变形虫功能的转变，也将使我们能够识别新的毒力因子，最终让我们能够定义疾病的基本机制。