The role of Salmonella protease PgtE in evading host immune responses

沙门氏菌蛋白酶 PgtE 在逃避宿主免疫反应中的作用

• 批准号: 10538295
• 负责人: Michael Hweemoon Lee
• 金额: $ 6.98万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10538295
• 关键词: Africa South of the Sahara; Antibiotic Resistance; Antibiotic Therapy; Antibiotics; Autophagocytosis; Autophagolysosome; Bacteremia; Bacterial Infections; Binding; Biological; Blood; Blood Circulation; Bypass; C3bi; Centers for Disease Control and Prevention (U.S.); Child; Complement; Complement 3b; Data; Defect; Diarrhea; Drug resistance; Elderly; Environment; Epidemic; Epithelial Cells; Exhibits; Gastrointestinal tract structure; Health; Host Defense; Immune response; Immune system; Immunocompromised Host; In Vitro; Individual; Infection; Inflammatory; Lead; Left; Mediating; Membrane; Morbidity - disease rate; Mucous Membrane; Mus; Myelogenous; Nutrient; O Antigens; Pathogenicity; Peptide Hydrolases; Peptides; Phagocytes; Phagocytosis; Phagolysosome; Phagosomes; Phase; Play; Prevalence; Proteins; Role; Salmonella; Salmonella enterica; Salmonella typhimurium; Signal Transduction; System; Systemic infection; Vaccines; Virulence; Virulence Factors; Virulent; Wild Type Mouse; Work; antimicrobial; antimicrobial peptide; arm; cobra venom factor; complement C3 precursor; complement system; cytokine; gastrointestinal bacteria; gastrointestinal epithelium; gut colonization; interleukin-22; intraperitoneal; macrophage; mortality; mutant; neutrophil; new therapeutic target; non-typhoidal Salmonella; novel; oral infection; overexpression; pathogen; post-doctoral training; prevent

Project Summary Bacterial infections remain a leading cause of morbidity and mortality worldwide and a critical health issue due to increasing antibiotic resistance and limited vaccines. Non-typhoidal Salmonella (NTS) serovars such as Salmonella enterica serovar Typhimurium (STm) are a leading cause of inflammatory diarrhea in otherwise healthy individuals, causing infections that are usually localized to the gut. Among immunocompromised individuals, children, and elderly, STm can cause a potentially lethal bacteremia that requires antibiotic treatment. Pivotal to innate host defense in preventing the spread of bacteria from the gastrointestinal tract to the bloodstream are antimicrobial peptides, complement system proteins, and phagocytic cells including macrophages and neutrophils. Pathogenic strains of STm can subvert the phagolysosome to survive intracellularly in macrophages, whereupon the autophagy system emerges as a critical step for killing intracellular STm. PgtE, a STm outer membrane protease, has been previously described to cleave over a dozen mammalian protein substrates in vitro, including complement protein C3, but these activities have only been observed with avirulent mutant strains possessing a defective outer membrane. In recent years, a newly emergent clade of invasive STm has been responsible for an epidemic of bacteremia in sub-Saharan Africa, with several studies suggesting an increased expression of PgtE as an important virulence mechanism although the mechanism remains unknown. Our preliminary studies suggest that PgtE plays an important role during infection in both the initial mucosal colonization and in the systemic phase with a virulent STm. Our central hypothesis is that after STm has been phagocytosed, STm utilizes PgtE to protect the disrupted outer membrane from antimicrobial peptides, complement, and autophagy killing, thereby promoting its survival in the host. In Aim 1, I will determine the role of PgtE in enabling STm to evade IL-22-mediated gut epithelial defenses after STm is phagocytosed in the lumen. In Aim 2, I will determine how PgtE subverts complement component C3 signaling and macrophage autophagic killing. This work will provide a framework on how pathogens utilize proteases to evade the immune system with potential novel therapeutic targets.

项目摘要 细菌感染仍然是全球发病率和死亡率的主要原因，以及关键的健康问题 由于抗生素耐药性增加和疫苗有限。非类型沙门氏菌（NTS）血清射手，例如 沙门氏菌血清鼠伤寒（STM）是炎症性腹泻的主要原因 健康的个体，导致通常局部局部的感染。在免疫功能低下 个体，儿童和老年人，STM可能会引起可能需要抗生素治疗的潜在致命菌血症。 与先天宿主防御的关键是防止细菌从胃肠道传播到 血液是抗菌肽，补体系统蛋白和吞噬细胞，包括 巨噬细胞和中性粒细胞。 STM的致病性菌株可以颠覆吞噬物体以生存 细胞内巨噬细胞，因此自噬系统是杀死细胞内的关键步骤 STM。 PGTE是一种STM外膜蛋白酶，以前已被描述为在十几个哺乳动物上裂。 体外蛋白质底物，包括补体C3，但仅观察到这些活性 具有缺陷的外膜的无毒突变菌株。近年来，新兴的进化枝 侵入性STM已导致撒哈拉以南非洲的菌血症流行，并进行了几项研究 提示PGTE表达增加为重要的毒力机制，尽管该机制 仍然未知。我们的初步研究表明，PGTE在感染中在两者中都起着重要作用 初始粘膜定殖和具有毒力STM的全身阶段。我们的中心假设是 STM已被吞噬，STM利用PGTE保护破坏的外膜免受抗菌剂的侵害 肽，补体和自噬杀死，从而促进了其在宿主中的生存。在AIM 1中，我将确定 PGTE在使STM逃避STM后逃避IL-22介导的肠上皮防御的作用 管腔。在AIM 2中，我将确定PGTE如何颠覆补体组件C3信号传导和巨噬细胞 自噬杀人。这项工作将为病原体如何利用蛋白酶逃避免疫力提供一个框架 具有潜在新型治疗靶标的系统。