N-terminal acylation and sorting of Helicobacter pylori lipoproteins and their role in host response to infection

幽门螺杆菌脂蛋白的 N 末端酰化和分选及其在宿主感染反应中的作用

• 批准号: 10447879
• 负责人: HOLLY Marie Scott ALGOOD
• 金额: $ 22.63万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-04 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10447879
• 关键词: ATP phosphohydrolase; Acids; Acylation; Affect; Animal Model; Anti-Inflammatory Agents; Antibiotic Resistance; Antibiotics; Bacteria; Bacterial Adhesion; Bacterial Infections; Binding Proteins; Biology; Cancer Etiology; Carcinogens; Cessation of life; Clarithromycin; Competence; Complex; Development; Disease; Enzymes; Epithelial Cells; Escherichia coli; Family; Foundations; Future; Gastritis; Goals; Gram-Negative Bacteria; Growth; Helicobacter Infections; Helicobacter pylori; Homologous Gene; Human; Hydrogen; Immune Tolerance; Immune response; Incidence; Infection; Inflammation; Inflammatory Response; Interferons; Lead; Length; Life; Lipoprotein (a); Lipoprotein Receptor; Lipoproteins; Malignant Neoplasms; Mammalian Cell; Membrane; Modification; Molecular; Mus; N-terminal; Oncoproteins; Orphan; Pathogenesis; Pattern; Peptic Ulcer; Periplasmic Proteins; Persons; Play; Population; Preventive therapy; Production; Proteins; Public Health; Resistance; Risk; Risk Factors; Role; Signal Transduction; Sorting - Cell Movement; Stomach; Stomach Diseases; Structure-Activity Relationship; System; TLR1 gene; TLR2 gene; TLR6 gene; Testing; Work; World Health Organization; antimicrobial; base; cancer site; cell motility; cyclopropane; design; immune activation; inhibitor; insight; malignant stomach neoplasm; mutant; novel; novel therapeutic intervention; pathogen; receptor; response

Project Summary (Abstract) Helicobacter pylori persistently colonizes the stomach in about 50% of the human population resulting in gastric inflammation and an increased risk of developing gastric diseases including cancer. The World Health Organization (WHO) lists gastric cancer as the third leading cause of cancer-related death worldwide and classifies H. pylori as a type I carcinogen. Increasing incidence of clarithromycin resistance also has led WHO to declare H. pylori a priority target for new antimicrobial development. Bacterial lipoproteins are modified by acylation to help anchor lipoproteins to the inner or outer membrane in Gram-negative bacteria. These proteins are an emerging target of antimicrobial development as inhibitors of bacterial lipoprotein synthesis or localization have been identified. H. pylori lipoproteins contribute to pathogenesis in numerous ways, including a role in delivering an oncoprotein (CagA) to mammalian cells. We hypothesize that lipoprotein sorting and modifications are fundamentally important for H. pylori immunopathogenesis. In previous studies, we showed that two of the three enzymes responsible for acylation of H. pylori lipoproteins and two proteins required for localization of lipoproteins to the inner vs outer membrane are essential for growth. In the current proposal, we will identify additional elements of the H. pylori lipoprotein localization system and determine the impact of H. pylori lipoproteins on immunopathogenesis. In Aim 1, we will characterize lipoprotein localization in H. pylori by identifying localization signals and previously unidentified proteins of the localization system. Further, lipoproteins are recognized by innate receptors of the host, leading to pro- or anti-inflammatory responses depending on the number and variety of acyl chain modifications on lipoproteins. Therefore, in Aim 2, we will determine how H. pylori lipoproteins influence immune cell activation and inflammation by characterizing the acyl chains present on H. pylori lipoproteins, defining how the number and variety of acyl chains affect innate signaling, and analyzing inflammation and disease in mice infected with H. pylori strains expressing tri- vs diacylated lipoproteins. The proposed studies will increase our understanding of lipoprotein biology and its impact on gastric disease thereby potentiating our ability to treat H. pylori infection and gastric cancer. Results will lay the foundation for future studies aimed at determining structure-activity relationships of novel lipoprotein localization components, antimicrobial development, and defining the role of lipoproteins and innate signaling in immune tolerance in H. pylori pathogenesis.

项目摘要（摘要）幽门螺杆菌持续定植于约 50% 的人类胃部 导致胃部炎症和患胃部疾病的风险增加的人群，包括 癌症。世界卫生组织（WHO）将胃癌列为癌症相关第三大原因 幽门螺杆菌在全球范围内死亡，并将其列为 I 型致癌物。克拉霉素耐药性的发生率增加 还导致世界卫生组织宣布幽门螺杆菌是新抗菌药物开发的优先目标。细菌脂蛋白 通过酰化进行修饰，以帮助将脂蛋白锚定到革兰氏阴性细菌的内膜或外膜上。 这些蛋白质是作为细菌脂蛋白抑制剂的抗菌药物开发的新兴目标 合成或定位已被确定。幽门螺杆菌脂蛋白以多种方式促进发病机制， 包括将癌蛋白（CagA）传递给哺乳动物细胞的作用。我们假设脂蛋白分选 和修饰对于幽门螺杆菌免疫发病机制至关重要。在之前的研究中，我们 研究表明，负责幽门螺杆菌脂蛋白酰化的三种酶中的两种以及所需的两种蛋白质 脂蛋白在内膜和外膜的定位对于生长至关重要。在目前的提案中， 我们将确定幽门螺杆菌脂蛋白定位系统的其他元件，并确定幽门螺杆菌的影响。 幽门螺杆菌脂蛋白对免疫发病机制的影响。在目标 1 中，我们将通过以下方式表征幽门螺杆菌中的脂蛋白定位： 识别定位信号和定位系统先前未识别的蛋白质。更远， 脂蛋白被宿主的先天受体识别，导致促炎或抗炎反应 取决于脂蛋白上酰基链修饰的数量和种类。因此，在目标 2 中，我们将 通过表征酰基来确定幽门螺杆菌脂蛋白如何影响免疫细胞激活和炎症 幽门螺杆菌脂蛋白上存在的链，定义了酰基链的数量和种类如何影响先天性 感染表达 tri-vs 的幽门螺杆菌菌株的小鼠中的信号转导和炎症和疾病分析 二酰化脂蛋白。拟议的研究将增加我们对脂蛋白生物学及其影响的理解 胃疾病，从而增强我们治疗幽门螺杆菌感染和胃癌的能力。结果将奠定 为未来研究确定新型脂蛋白的结构-活性关系奠定基础 定位成分、抗菌剂开发以及定义脂蛋白和先天信号传导的作用 幽门螺杆菌发病机制中的免疫耐受。