The role of Entamoeba histolytica trogocytosis (trogo-: nibble) in the pathogenesis of amoebiasis

溶组织内阿米巴 trogocytosis（trogo-：nibble）在阿米巴病发病机制中的作用

• 批准号: 10158434
• 负责人: Katherine S Ralston
• 金额: $ 37.16万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-06-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10158434
• 关键词: Abscess; Actins; Address; Amoeba genus; Animal Model; Animals; Biology; Blood; Brain; Cell Communication; Cell Membrane Proteins; Cells; Chemotaxis; Child; Complement; Cytochalasin D; Cytolysis; Defect; Development; Dual-role transvestism; Entamoeba histolytica; Eukaryota; Eukaryotic Cell; Flow Cytometry; Human; Image; Immune; Immune Evasion; Immune system; In Vitro; Ingestion; Intestines; Invaded; Knowledge; Large Intestine; Liver; Lung; Lytic; Mediating; Membrane Proteins; Microbe; Modeling; Morbidity - disease rate; Mus; Names; Nature; Neuraxis; Pathogenesis; Phagocytosis; Play; Principal Investigator; Proteins; Proteomics; Resistance; Role; Serum; Source; Surface; Testing; Tissues; Ulcer; Work; animal imaging; cell killing; cell type; diarrheal disease; genetic regulatory protein; improved; in vivo; innovation; microbial; mouse model; mutant; neutrophil; novel strategies; pathogen; professional atmosphere

Abstract Entamoeba histolytica is a protozoan pathogen and the causative agent of amoebiasis in humans. The species name (histo-: tissue; lytic-: dissolving) derives from the ability to destroy host tissues. E. histolytica trophozoites (“amoebae”) invade the large intestine, causing ulceration and can spread to other tissues (e.g., liver, lungs, brain), causing fatal abscesses. Amoebae possess contact-dependent cell-killing activity that is likely to drive tissue damage, but the mechanism was unclear. We established a new paradigm by discovering that amoebae kill by biting off and ingesting human cell fragments, which we named “amoebic trogocytosis” (trogo-: nibble) (Ralston, et al., Nature, 2014). Building on this discovery, here we propose to delineate the unexpected contribution of trogocytosis to immune evasion. We will apply imaging flow cytometry, host and amoeba mutants, and a variety of host cell types to dissect the contribution of trogocytosis to immune avoidance in vitro, and we will use the mouse model of amoebiasis to extend these findings to pathogenesis in vivo. Beyond E. histolytica, trogocytosis has far-reaching applications to eukaryotic biology. Several microbial eukaryotes appear to use trogocytosis for cell-killing. In multicellular eukaryotes, trogocytosis is used for cell-killing, cell-cell communication and cell-cell remodeling. Trogocytosis plays roles in the immune system, in the central nervous system, and during development. Therefore, an improved understanding of the mechanism and biology of E. histolytica trogocytosis will apply both directly to the pathogenesis of amoebiasis and broadly to eukaryotic trogocytosis in general. This work is significant and high-impact as it will define a novel strategy for immune evasion and an important aspect of amoebiasis pathogenesis. Moreover, these studies apply broadly to trogocytosis as a conserved mode of eukaryotic cell-cell interaction. !

抽象的 溶组织内阿米巴是一种原生动物病原体，也是人类阿米巴病的病原体。 种名（组织-：组织；溶解-：溶解）源自破坏宿主组织的能力。 滋养体（“变形虫”）侵入大肠，引起溃疡并可以扩散到其他组织（例如， 肝、肺、脑），导致致命的脓肿，变形虫可能具有接触依赖性细胞杀伤活性。 驱动组织损伤，但其机制尚不清楚，我们发现了这一点，建立了一个新的范例。 阿米巴变形虫通过咬断和摄入人类细胞碎片来杀死人类，我们将其命名为“阿米巴变形细胞作用”（trogo-： nibble）（Ralston 等人，Nature，2014）。在此发现的基础上，我们建议描述 我们将应用成像流式细胞术、宿主和免疫逃避的意想不到的贡献。 阿米巴突变体和多种宿主细胞类型来剖析吞噬作用对免疫回避的贡献 在体外，我们将使用阿米巴病小鼠模型将这些发现扩展到体内发病机制。 E. histolytica，trogocytosis 在真核生物学中具有深远的应用。 似乎使用 trogocytosis 来杀死细胞 在多细胞真核生物中，trogocytosis 用于细胞杀伤，细胞间的。 通讯和细胞间重塑在免疫系统和中枢神经系统中发挥作用。 系统，并在开发过程中，加深了对大肠杆菌的机制和生物学的了解。 溶组织细胞增多症将直接应用于阿米巴病的发病机制，并广泛应用于真核生物 这项工作意义重大且影响深远，因为它将定义一种新的策略。 此外，这些研究也适用于免疫逃避和阿米巴病发病机制的一个重要方面。 广义上来说，trogocytosis 是真核细胞与细胞相互作用的一种保守模式。 ！