Effector-triggered immunity against Legionella pneumophila in dendritic cells

树突状细胞中针对嗜肺军团菌的效应子触发免疫

基本信息

批准号：
10753211
负责人：
Sunny Shin
金额：
$ 24.06万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-07-05 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10753211
关键词：
Ablation Anti-Bacterial Agents Antibiotic Resistance Apoptosis Autoimmune Diseases BCL2 gene Bacterial Infections Biochemical CASP3 gene CASP8 gene Cell Death Cells Crohn&apos s disease Data Dendritic Cells Development Disease Family member Genetic Goals Hospitals Host Defense Host Defense Mechanism Humira Immune Immune response Immunity Immunocompromised Host Immunosuppressive Agents In Vitro Individual Induction of Apoptosis Infection Infection Control Inhalation Inhibition of Apoptosis Innate Immune Response Integration Host Factors Legionella Legionella pneumophila Legionnaires&apos Disease Licensing Lung Lung infections Macrophage Mediating Medical Molecular Mus Mycobacterium tuberculosis Natural Immunity Patients Play Protein Biosynthesis Protein Family Psoriasis Public Health Rheumatoid Arthritis Risk Role Salmonella Signal Transduction TNF gene Testing Therapeutic Time Translations Type IV Secretion System Pathway Ulcerative Colitis United States antimicrobial burden of illness community acquired pneumonia contaminated water defined contribution gain of function immunosuppressed improved in vivo infection risk infliximab inhibitor insight loss of function mutant novel novel therapeutics opportunistic pathogen pathogen pathogenic bacteria permissiveness pharmacologic response targeted treatment therapeutic development

项目摘要

Project Summary Intracellular bacterial pathogens such as Legionella pneumophila, the causative agent of the severe pneumonia Legionnaires' disease, are responsible for significant disease burden in the United States every year. The growing use of immunosuppressive drugs, particularly TNF blockrs, to treat autoimmune diseases comes with a significantly increased risk of infection by intracellular bacterial pathogens, including Mycobacterium tuberculosis and Legionella pneumophila. The increasing numbers of individuals who are functionally immunocompromised due to growing use of TNF blockade, combined with the growing spread of antibiotic resistance, poses a serious public health concern. Our goal is to define the mechanisms by which TNF promotes immune defense against Legionella pneumophila. This information may enable development of targeted therapeutics that promote anti- bacterial defense in immunocompromised individuals. Critically, in new preliminary studies that take advantage of our ability to dissect the interactions between Legionella and dendritic cells, we find that TNF signaling drives a Legionella effector-triggered immune response that induces apoptosis in dendritic cells, thereby restricting intracellular Legionella replication. The proposed studies will provide fundamental insight into how TNF-mediated effector-triggered immunity promotes control of intracellular Legionella replication within dendritic cells. This information may provide a basis for the development of improved therapeutics for the treatment of Legionella and other bacterial pathogens.

项目摘要细胞内细菌病原体，例如肺炎军团菌，严重肺炎的病因军团疾病每年都会导致美国造成重大疾病负担。这越来越多地使用免疫抑制药物，尤其是TNF阻滞，以治疗自身免疫性疾病细胞内细菌病原体感染的风险显着增加，包括结核分枝杆菌和军团肺炎。功能免疫功能低下的个体数量越来越多由于TNF阻滞的使用不断增长，并结合了抗生素耐药性的增长，因此构成了严重的公共卫生问题。我们的目标是定义TNF促进免疫防御的机制军团肺炎。这些信息可能会发展有针对性的治疗剂，以促进抗免疫功能低下的个体中的细菌防御。至关重要的是，在利用优势的新初步研究中我们剖析军团菌与树突状细胞之间相互作用的能力，我们发现TNF信号驱动诱导树突状细胞凋亡的军团菌效应触发的免疫反应，从而限制细胞内军团菌复制。拟议的研究将为TNF介导的如何提供基本的见解效应触发的免疫可促进对树突状细胞内细胞内军团内复制的控制。这信息可以为开发改进的治疗治疗的治疗方法提供基础和其他细菌病原体。