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.

项目概要 细菌感染仍然是全球发病率和死亡率的主要原因，也是一个严重的健康问题 由于抗生素耐药性增加和疫苗有限。非伤寒沙门氏菌 (NTS) 血清型，例如 肠沙门氏菌鼠伤寒血清型 (STm) 是其他疾病中炎症性腹泻的主要原因 健康个体，引起通常局限于肠道的感染。免疫功能低下者中 对于个人、儿童和老年人，STm 可能会导致潜在致命的菌血症，需要抗生素治疗。 对于防止细菌从胃肠道传播到肠道的先天宿主防御至关重要 血液中含有抗菌肽、补体系统蛋白和吞噬细胞，包括 巨噬细胞和中性粒细胞。 STm 致病菌株可以破坏吞噬溶酶体以生存 在巨噬细胞的细胞内，自噬系统成为杀死细胞内巨噬细胞的关键步骤。 STm。 PgtE 是一种 STm 外膜蛋白酶，此前已被描述可裂解十多种哺乳动物 体外蛋白质底物，包括补体蛋白 C3，但这些活性仅在 外膜有缺陷的无毒突变株。近年来，一个新出现的分支 多项研究表明，侵入性 STm 是撒哈拉以南非洲地区菌血症流行的原因 表明 PgtE 表达增加是一种重要的毒力机制，尽管该机制 仍然未知。我们的初步研究表明 PgtE 在感染过程中发挥着重要作用 最初的粘膜定植和全身阶段具有剧毒的 STm。我们的中心假设是，之后 STm 已被吞噬，STm 利用 PgtE 保护受损的外膜免受抗菌药物的侵害 肽、补体和自噬杀伤，从而促进其在宿主中的存活。在目标 1 中，我将确定 STm 被吞噬后，PgtE 在使 STm 逃避 IL-22 介导的肠上皮防御中的作用 流明。在目标 2 中，我将确定 PgtE 如何破坏补体成分 C3 信号传导和巨噬细胞 自噬杀伤。这项工作将为病原体如何利用蛋白酶逃避免疫系统提供一个框架。 具有潜在新治疗靶点的系统。