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: 10404102
• 负责人: Katherine S Ralston
• 金额: $ 17.67万
• 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/10404102
• 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. !

摘要 溶组织内阿米巴是一种原生动物病原体，是人类阿米巴病的病原体。的 种名（histo-：组织; lytic-：溶解）来源于破坏宿主组织的能力。E. histolytica 滋养体（“阿米巴”）侵入大肠，引起溃疡并可扩散到其它组织（例如， 肝、肺、脑），导致致命的中毒。变形虫具有接触依赖性细胞杀伤活性， 导致组织损伤，但其机制尚不清楚。我们建立了一个新的范式， 变形虫通过咬下和吞噬人类细胞碎片来杀死人，我们将其命名为“变形虫胞饮症”（trogo-： 蚕食）（Ralston，等人，Nature，2014）。基于这一发现，我们在这里提出描绘 胞啃作用对免疫逃避的意想不到的贡献。我们将应用成像流式细胞术，主机和 变形虫突变体和各种宿主细胞类型，以剖析胞刺对免疫回避的贡献 在体外，我们将使用阿米巴病的小鼠模型，以扩大这些发现在体内的发病机制。超出 E. trogocytica在真核生物学中具有深远的应用。几种微生物真核生物 似乎是利用胞洞作用杀死细胞。在多细胞真核生物中，胞间刺胞作用用于细胞杀伤、细胞-细胞 通讯和细胞间重塑。胞饮在免疫系统和中枢神经中发挥作用 系统和开发过程中。因此，进一步了解E. 溶组织性胞啃作用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 一般来说，这项工作意义重大，影响深远，因为它将为 免疫逃避和阿米巴病发病机制的一个重要方面。此外，这些研究适用于 广义地说，胞啃作用是真核细胞-细胞相互作用的保守模式。 !