Defining how Entamoeba histolytica nibbles vs. devours human cells

定义溶组织内阿米巴如何蚕食与吞噬人类细胞

• 批准号: 10043675
• 负责人: Katherine S Ralston
• 金额: $ 21.92万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-01 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10043675
• 关键词: Abscess; Address; Amoeba genus; Bioinformatics; Biological Assay; Biology; Brain; Caenorhabditis elegans; Candidate Disease Gene; Cell Communication; Cells; Child; Data; Defect; Development; Dynamin; Embryonic Development; Entamoeba histolytica; Ephrins; Eukaryota; Genes; Genetic; Genetic Screening; Genomics; Human; Immune system; Infection; Ingestion; Intestines; Invaded; Knowledge; Large Intestine; Libraries; Literature; Liver; Lung; Lytic; Membrane; Microbe; Morbidity - disease rate; Names; Nature; Neuraxis; Organism; Pathogenesis; Phagocytosis; Phenotype; Plasmids; Play; Process; Proteins; RNA Interference; Role; Source; Tissues; Toxin; Transcriptional Regulation; Ulcer; Work; base; cell killing; deep sequencing; diarrheal disease; feeding; forward genetics; genetic selection; genome-wide; improved; innovation; knock-down; macrophage; microbial; mutant; pathogen; professional atmosphere; tool; transcriptomics

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 its underlying mechanism. Trogocytosis is likely to share features with phagocytosis, since many proteins with roles in phagocytosis are also required for trogocytosis. However, there are emerging hints that aspects of the trogocytosis mechanism are distinct. Thus, we hypothesize that aspects of the trogocytosis mechanism are distinct from phagocytosis. We will apply genetic and transcriptomic approaches to delineate the genes that are shared between trogocytosis and phagocytosis, and those that are specific to each process. 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 have a broad impact beyond amoebiasis. This work is significant and high-impact as it will define the mechanism underlying trogocytosis and how it differs from phagocytosis. Our approaches will also generate valuable new genetic tools. Moreover, our findings will apply directly to amoebiasis pathogenesis, and broadly to other infections and the conserved process of trogocytosis. !

摘要 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。这个 物种名称(组织-：组织；溶解-：溶解)源于破坏宿主组织的能力。组织裂殖吸虫 滋养体(“阿米巴”)侵入大肠，引起溃疡并可扩散到其他组织(例如， 肝、肺、脑)，导致致命的脓肿。阿米巴具有接触性细胞杀伤活性，很可能 以推动组织损伤，但其机制尚不清楚。我们建立了一个新的范式，通过发现 阿米巴虫通过咬下和吞食人类细胞碎片来杀死人，我们将其命名为阿米巴滋养细胞增多症(trogo-： 半截)(Ralston等人，《自然》，2014年)。在这一发现的基础上，我们建议在这里描绘它的 潜在的机制。巨噬细胞增多症可能与吞噬作用有共同的特征，因为许多具有 巨噬细胞增多症也需要在吞噬中发挥作用。然而，有新的迹象表明， 巨噬细胞增多症的发生机制各不相同。因此，我们假设巨噬细胞增多症机制的某些方面是 不同于吞噬作用。我们将应用遗传学和转录学的方法来描绘 是巨噬细胞增多和吞噬作用所共有的，也是每个过程特有的。超越E. 组织溶解、巨噬细胞增多症在真核生物学中有着深远的应用。出现了几种微生物真核生物 用巨噬细胞增多症来杀死细胞。在多细胞真核生物中，巨噬细胞增多症用于杀死细胞、细胞间 沟通和细胞-细胞重塑。巨噬细胞增多症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。因此，对E. 溶组织性巨噬细胞增多症的影响将超越阿米巴病。这项工作意义重大，影响深远。 因为它将定义巨噬细胞增多的潜在机制，以及它与吞噬作用有何不同。我们的 这些方法还将产生有价值的新基因工具。此外，我们的发现将直接适用于 阿米巴病的发病机制，以及广泛到其他感染和巨噬细胞增多症的保守过程。 好了！