Effect of Bacterial Tolerance on TLR4 Signal Transduction

细菌耐受性对 TLR4 信号转导的影响

• 批准号: 7064266
• 负责人: ANDREI E MEDVEDEV
• 金额: $ 32.63万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-05-15 至 2010-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7064266
• 关键词: alcohol phosphotransferase; biological signal transduction; clinical research; host organism interaction; human subject; immune response; immune tolerance /unresponsiveness; lipopolysaccharides; microorganism immunology; monocyte; posttranslational modifications; protein protein interaction; receptor expression; septicemia; toll like receptor

DESCRIPTION (provided by applicant): Despite advances of modern medicine, bacterial sepsis remains one of the major threats to human health worldwide. In the U.S.A alone, it affects approximately 750,000 Americans per year, with an associated mortality rate >28%. The lipopolysaccharide (LPS), an outer membrane component of Gram negative bacteria, and various structures of Gram positive bacteria and Mycobacterium tuberculosis, represent the initiating stimuli in the activation of the innate immune response. Effective recognition of these bacterial structures by Toll-like receptors (TLR) expressed on monocytes and macrophages is critical for mounting a strong first line defense and prevention of sepsis. Many patients with sepsis develop a hypoinflammatory state that is manifested by marked inhibition of monocyte functions, including suppressed production of a number of cytokines. This state is highly reminiscent of bacterial tolerance defined as a transient state of cell refractoriness following a prior exposure to bacterial components. Therefore, induction of bacterial tolerance can be used as a model to delineate mechanisms that underlie decreased monocyte responsiveness in patients with sepsis. Despite numerous studies, the molecular mechanisms that underlie induction of bacterial tolerance are still largely unknown. The overall goal of this project is to gain a better understanding of the molecular mechanisms of host responses to microbes. Our objective is to define the role of receptors and signal transducing molecules of the TLR pathway in induction and maintenance of bacterial tolerance in monocytes. The central hypothesis is that induction of bacterial tolerance in human monocytes dramatically alters signal-induced complex formation among key components of the TLR pathway, leading to development of a state of suppressed antibacterial responsiveness. The following Specific Aims are proposed to: 1. Examine post-translational modifications and interactions of key molecules of TLR4 complexes associated with tolerance to TLR4 and TLR2 agonists. 2. Analyze the effect of bacterial tolerance on expression, recruitment, post-translational modifications of key adapter proteins and activation of IRAK-4. 3. Characterize suppressors of TLR-mediated signaling in tolerized cells that interfere with agonist-induced interactions among TLRs, adapter proteins, and IRAK kinases. It is expected that at the completion of this grant, we will have identified key molecular mechanisms responsible for development of bacterial tolerance, and have provided strategies for development of new therapeutic approaches for treatment of patients with bacterial sepsis to target components of the TLR signaling pathway that are compromised in tolerance and sepsis.

描述（由申请人提供）：尽管有现代医学的进步，但细菌败血症仍然是全球人类健康的主要威胁之一。仅在美国，它每年就会影响约75万美国人，相关死亡率> 28％。脂多糖（LPS）是革兰氏阴性细菌的外膜成分，以及革兰氏阳性细菌和结核分枝杆菌的各种结构，代表了在激活先天免疫反应激活的启动刺激。通过单核细胞和巨噬细胞表达的Toll样受体（TLR）对这些细菌结构的有效识别对于安装强烈的第一线防御和预防败血症至关重要。许多败血症患者会出现低炎性状态，这表现为单核细胞功能的明显抑制，包括抑制多种细胞因子的产生。该状态高度让人联想到细菌耐受性，该耐受性定义为先前暴露于细菌成分后的细胞耐磨性的瞬时状态。因此，可将细菌耐受性的诱导用作描述败血症患者单核细胞反应性降低的机制的模型。尽管进行了许多研究，但基于诱导细菌耐受性的分子机制仍然在很大程度上未知。该项目的总体目标是更好地了解宿主对微生物的分子机制。我们的目的是定义受体和信号转导途径在单核细胞中细菌耐受性的诱导和维持中的作用。中心假设是，人类单核细胞中细菌耐受性的诱导极大地改变了TLR途径的关键成分之间信号诱导的复合物的形成，从而导致抑制抗菌反应的状态发展。提出以下特定目的：1。检查与TLR4和TLR2激动剂耐受性相关的TLR4复合物的关键分子的关键分子的相互作用。 2。分析细菌耐受性对关键衔接蛋白的表达，募集后翻译后修饰和IRAK-4激活的影响。 3。表征TLR介导的信号传导在公差细胞中的抑制剂，这些信号传导干扰了激动剂诱导的TLR，衔接蛋白和IRAK激酶之间的相互作用。可以预期，该赠款完成后，我们将确定负责开发细菌耐受性的关键分子机制，并为开发新的治疗方法提供了用于治疗细菌败血症患者的新治疗方法，以靶向TLR信号途径的TLR信号途径的组成部分，这些途径在耐受性和SEPIS中受到损害。