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

描述(申请人提供)：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寄生虫感染，也是儿童发病率和死亡率的主要来源。溶组织内阿米巴因其对宿主组织的破坏和对肠道的侵袭而被称为“溶组织阿米巴”，但其作用机制尚不清楚。我最近有了一个令人惊讶的发现，阿米巴通过咬下和吞噬不同的活细胞片段来杀死人，导致细胞内钙升高并最终死亡。我将其命名为“巨噬细胞增多症”(希腊语，trogo-：nibble)，因为它与免疫细胞中的巨噬细胞增多症相似。我推测阿米巴结肠炎的病理是由寄生虫通过蚕食肠道上皮细胞入侵肠道所致。很可能这部小说 杀伤机制需要独特的吞噬机制，而且这些成分代表着新的药物靶点。因此，我建议揭示巨噬细胞增多症样摄取的信号机制。此外，我建议重新检验长期存在的假设，即溶解组织埃希氏菌的孔洞形成蛋白，也就是众所周知的“阿米巴前体”，是分泌的细胞毒效应因子。这项工作的成功完成将在阿米巴变形器的功能上创造一个范式转换，还将使我们能够识别新的毒力因子，最终允许 我们来定义疾病的基本机制。

DESCRIPTION (provided by applicant): 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 functio of the amoebapores, and will also allow us to identify novel virulence factors, ultimately allowing us to define the basic mechanism of disease.