The mechanism and role of erythrocyte invasion by Francisella tularensis

土拉弗朗西斯菌侵袭红细胞的机制及作用

• 批准号: 10730228
• 负责人: JOSEPH A HORZEMPA
• 金额: $ 42.15万
• 依托单位: WEST LIBERTY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-05-01 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10730228
• 关键词: ANK1 gene; Animals; Antibiotics; Arbovirus Infections; Arthropod Vectors; Arthropods; Bacteria; Bacterial Proteins; Binding; Binding Proteins; Biochemistry; Biological; Biology; Bite; Blood; Categories; Cell Surface Proteins; Cells; Centers for Disease Control and Prevention (U.S.); Complex; Cytoskeleton; Dangerousness; Data; Dermacentor; Disease; Disease Vectors; Epithelial Cells; Erythrocyte Anion Exchange Protein 1; Erythrocyte Membrane; Erythrocytes; Fibroblasts; Francisella; Francisella tularensis; Funding; Hepatocyte; Immune system; Immunity; In Vitro; Infection; Infectious Agent; Inhalation; Invaded; Investigation; Knowledge; Laboratories; Life; Link; Macrophage; Mammals; Manuscripts; Mediating; Membrane Proteins; Molecular; Molecular Genetics; Mus; Organism; Pathogenesis; Phagocytes; Planet Earth; Principal Investigator; Proliferating; Protein Secretion; Proteins; Publications; Research; Role; Seminal; Site; Spectrin; System; Testing; Ticks; Tularemia; Virulent; Work; Zoonoses; alveolar epithelium; biodefense; cell type; combat; extracellular; host-microbe interactions; insight; neutrophil; novel; pathogen; pathogenic bacteria; programs; sucking; tick feeding; transmission process

Francisella tularensis is one of the most infectious organisms as inhalation of a single bacterium can lead to a fatal disease referred to as tularemia. It has therefore been categorized by the Centers for Disease Control and Prevention as a Category A biodefense agent. Many seminal studies have shown that the ability of F. tularensis to replicate within macrophages is associated with the pathogenesis of this organism. In subsequent years, my laboratory helped to move the field of Francisella research forward by illuminating that interactions with non- macrophages are also extremely important during infection as these cells provide a sanctuary from immunity, allow for bacterial proliferation, and provide protection from antibiotics. Although much of the work in the field of F. tularensis has focused on the intra-macrophage biology of this organism, interactions with other cell types have not been thoroughly investigated. Perhaps the most surprising finding of our laboratory was the discovery that F. tularensis invades and persists in erythrocytes. This invasion enhances the ability of F. tularensis bacteria to survive in ticks (important disease vectors) following a blood meal. In this application, we will test the hypothesis that erythrocyte invasion is required for long-term colonization of ticks and subsequent transmission to mammals. We have previously shown that the erythrocyte surface protein, Band 3 is required for invasion and that interaction with this surface protein may be required for manipulation of the spectrin cytoskeleton through Ankyrin-1. Moreover, we have shown that F. tulareniss bacteria secrete PdpC into erythroyctes via the type VI secretion system (T6SS), and that this effector is required for invasion. OpiA, another T6SS effector, is produced and accumulates in erythrocytes during bacterial persistence. In this application, we will explore these aforementioned host and bacterial proteins to gain insight into the mechanism of erythrocyte invasion and the persistence within these host cells.

土拉弗朗西斯菌是最具传染性的生物体之一，吸入一次 细菌可导致一种称为兔热病的致命疾病。因此被分类为 被疾病控制和预防中心列为 A 类生物防御剂。许多 开创性的研究表明 F. tularensis 在巨噬细胞内复制的能力 与该生物体的发病机制有关。在随后的几年里，我的实验室帮助 通过阐明与非-弗朗西斯菌的相互作用，推动弗朗西斯菌研究领域向前发展 巨噬细胞在感染过程中也极其重要，因为这些细胞提供了庇护所 免受免疫，允许细菌增殖，并提供抗生素保护。虽然 F. tularensis 领域的大部分工作都集中在其巨噬细胞内生物学上 有机体与其他细胞类型的相互作用尚未得到彻底研究。或许是 我们实验室最令人惊讶的发现是发现 F. tularensis 入侵并持续存在 在红细胞中。这种入侵增强了土拉菌细菌在蜱中的生存能力 （重要的疾病媒介）血餐后。在此应用中，我们将检验假设 蜱虫的长期定植和后续的定植需要红细胞入侵 传播给哺乳动物。 我们之前已经表明，红细胞表面蛋白 Band 3 是 入侵并且与该表面蛋白的相互作用可能是操纵 通过 Ankyrin-1 血影蛋白细胞骨架。此外，我们还发现 F. tulareniss 细菌 通过 VI 型分泌系统 (T6SS) 将 PdpC 分泌到红细胞中，并且该效应子是 入侵所需。 OpiA 是另一种 T6SS 效应物，在红细胞中产生并积累 在细菌持续存在期间。在此应用程序中，我们将探索上述主机和 细菌蛋白以深入了解红细胞侵袭的机制及其持续性 在这些宿主细胞内。