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.

项目概要细胞内细菌病原体，例如嗜肺军团菌（重症肺炎的病原体）退伍军人病每年在美国造成重大疾病负担。这越来越多地使用免疫抑制药物，特别是 TNF 阻滞剂来治疗自身免疫性疾病，伴随着细胞内细菌病原体（包括结核分枝杆菌）感染的风险显着增加和嗜肺军团菌。功能性免疫功能低下的人数不断增加由于 TNF 阻断剂的使用越来越多，加上抗生素耐药性的日益蔓延，造成了严重的公共卫生问题。我们的目标是确定 TNF 促进免疫防御的机制嗜肺军团菌。这些信息可能有助于开发靶向治疗药物，以促进抗- 免疫功能低下个体的细菌防御。至关重要的是，在新的初步研究中，利用凭借我们剖析军团菌和树突状细胞之间相互作用的能力，我们发现 TNF 信号驱动军团菌效应子触发的免疫反应诱导树突状细胞凋亡，从而限制军团菌细胞内复制。拟议的研究将为 TNF 介导的机制提供基本见解效应子触发的免疫促进树突状细胞内军团菌复制的控制。这该信息可能为开发治疗军团菌的改进疗法提供基础和其他细菌病原体。