Toll-Like Receptors and Immunity to F. tularensis

Toll 样受体和对土拉弗拉菌的免疫

基本信息

批准号：
7662476
负责人：
MICHAEL T BERTON
金额：
$ 32.44万
依托单位：
UNIVERSITY OF TEXAS SAN ANTONIO
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/7662476
关键词：
Address Aerosols Alveolar Macrophages Antibiotics Attenuated Attenuated Live Virus Vaccine Attenuated Vaccines Cells Cessation of life Communicable Diseases Data Defect Development Disease Dose Early Diagnosis Francisella Francisella tularensis Future Genes Genotype Goals Gram-Negative Bacteria Growth Human Immune Immune response Immunity In Situ In Vitro Infection Inflammatory Knowledge Lethal Dose 50 Licensing Lung Mediating Modeling Mus Mutation Natural Immunity Nature Organism Oxygen Pathogenicity Pattern Pattern recognition receptor Phagocytosis Phenotype Play Polymerase Chain Reaction Population Predisposition Principal Investigator Production Proteins Publishing Range Reagent Receptor Signaling Research Response Elements Risk Role Series Shapes Signal Pathway Signal Transduction Signaling Molecule Systemic infection TLR2 gene Testing Time Tissues Toll-like receptors Tularemia Vaccine Adjuvant Vaccines Virulence Virulent Work aerosolized attenuation chemokine cytokine expectation in vivo insight knock-down macrophage microorganism mouse model mutant novel vaccines pathogen programs response

项目摘要

PROJECT 3 DESCRIPTION (provided by applicant): Francisella tularensis is a gram-negative bacterium that is the causative agent of tularemia, a highly infectious disease that can be fatal in humans, particularly in the pneumonic form. F. tularensis is an ideal bioweapon because of its extremely low LD50 and ease of aerosol dissemination. The disease is treatable with antibiotics if diagnosed early, but there is no licensed vaccine currently available and, therefore the population is at considerable risk in case of mass exposure. Many studies have focused on immunity to an attenuated live vaccine strain (LVS) derived from F. tularensis subsp. holoarctica, but virtually nothing is known about the immune response during pneumonic tularemia caused by the highly virulent F. tularensis subsp. tularensis. Toll-like receptors (TLRs) are critical innate immunity response elements that serve as a first line of defense by recognizing conserved, repeated patterns in molecules expressed by many pathogens. TLRs signal cells of the innate response and shape subsequent adaptive immunity by inducing expression of chemokines, pro-inflammatory cytokines and co-stimulatory molecules and thus are important targets for new adjuvants and vaccines. Our preliminary studies demonstrate a defect in the ability of primary alveolar macrophages from MyD88 mice to secrete TNF-a upon infection with F. tularensis LVS and increased susceptibility of MyD88-/- and TLR2-/- mice to LVS infection. Recent published studies suggest that F. tularensis may evade host innate immune responses. The central hypothesis for the proposed work is that activation/inhibition of TLR signaling plays a critical role in determining the nature of the innate response in the lung to aerosol infection by virulent F. tularensis. The proposed studies will test this hypothesis in an aerosol infection model of pneumonic tularemia in the mouse. We will 1) determine the role of TLR signaling in the host response to pulmonary infection with F. tularensis subsp. tularensis (Schu4) using KO mice and SiRNA; 2) identify and characterize TLR-regulated immune effector mechanisms that are involved in the innate response to pulmonary tularemia; and 3) define TLR signal-modulating mechanisms by which F. tularensis evades the host innate immune response. We expect that these studies will provide significant advances in our understanding of the overall immunopathogenesis of virulent F. tularensis and will provide critical insight into the role of Toll-like receptors in the host innate response to pneumonic tularemia.

项目3描述（由申请人提供）：弗朗西斯拉·蒂拉西斯（Francisella tularensis）是革兰氏阴性细菌是Tularemia的病因，一种高度感染性疾病，可能致命人类，尤其是肺炎形式。 F. tularensis是理想的生物武器 LD50极低，气溶胶传播的便利性。该疾病可以用抗生素治疗，如果被诊断为抗生素，但是目前没有持牌疫苗，因此，在大规模暴露时，人口的风险很大。许多研究集中在对源自F. tularensis subsp的衰减活疫苗菌株（LVS）的免疫力上。 Holoarctica，但实际上对高度毒性的F. tularensis subsp引起的肺炎肺炎期间的免疫反应一无所知。 tularensis。 Toll样受体（TLR）是关键的先天免疫反应元件，通过识别许多病原体表达的分子中保守的，重复的模式，作为第一道防线。通过诱导趋化因子的表达，促炎性细胞因子和共刺激性分子的表达，TLRS信号细胞和随后的适应性免疫，因此是新佐剂和疫苗的重要靶标。我们的初步研究表明，在感染F. tularensis lvs感染后，从MyD88小鼠中原发性肺泡巨噬细胞分泌TNF-A的能力缺陷，MyD88 - / - / - 和TLR2 - / - 小鼠的易感性提高到LVS感染。最近的已发表的研究表明，tularensis可能会逃避宿主先天免疫反应。拟议工作的中心假设是，TLR信号传导的激活/抑制在确定毒性F. tularensis肺对气溶胶感染中先天反应的性质方面起着关键作用。拟议的研究将在小鼠中肺炎的气溶胶感染模型中检验该假设。我们将1）确定TLR信号在宿主对肺部感染的宿主反应中的作用。使用KO小鼠和siRNA的Tularensis（Schu4）； 2）识别和表征与天生对肺部血症的先天反应有关的TLR调节的免疫效应机制； 3）定义了TLR信号调节机制，f。tularensis逃避了宿主先天免疫反应。我们预计这些研究将在我们对毒性f菌的总体免疫病作用方面的理解方面带来重大进展，并将为Toll样受体在宿主对肺炎的天生反应中的作用提供关键的见解。