Role of Toll-like Receptors 3 and 4 in Viral Heart Disease

Toll 样受体 3 和 4 在病毒性心脏病中的作用

• 批准号: 7459228
• 负责人: JESUS G VALLEJO
• 金额: $ 30.7万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-10 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7459228
• 关键词: Acute; Acute Myocarditis; Adaptor Signaling Protein; Adult; Antiviral Agents; Antiviral Response; Apoptosis; Apoptotic; Arrhythmia; C-terminal; CXCL10 gene; Cardiac; Cardiac Myocytes; Cells; Cessation of life; Child; Childhood; Clinical; Complex; Country; Cytoprotection; Data; Development; Dilatation - action; Dilated Cardiomyopathy; Disease; Disruption; Elements; Encephalomyocarditis virus; Enterovirus; Family; Grant; Heart; Heart Diseases; Heart Transplantation; Heart failure; Host Defense; Immune response; Immune system; Immunologic Receptors; In Vitro; Infant; Infection; Injury; Interferons; Interleukin-1; Interleukin-1 Receptors; Laboratories; Lead; Left; Ligand Binding; Mediating; Mediator of activation protein; Morbidity - disease rate; Mus; Muscle Cells; Myelogenous; Myocardial; Myocarditis; Myocardium; N-terminal; Neonatal; Nitric Oxide; North America; Pathological Dilatation; Pathway interactions; Patients; Production; Protein Overexpression; Public Health; RANTES; Rattus; Receptor Signaling; Role; Signal Pathway; Signal Transduction; Structure; Sudden Death; T-Lymphocyte; TLR3 gene; TLR4 gene; Testing; Tissues; Toll-Like Receptor 5; Toll-like receptor 6; Toll-like receptors; Tumor Necrosis Factor-alpha; Tumor Necrosis Factors; Ventricular; Viral; Viral Cytopathogenic Effect; Virus; Virus Diseases; Virus Replication; base; biological adaptation to stress; caspase-8; cytokine; human TLR3 protein; human TNF protein; improved; in vivo; loss of function; microbial; mortality; pathogen; prevent; promoter; protective effect; receptor; sensor; young adult

DESCRIPTION (provided by applicant): Viral infections of the heart are among the most commonly identified causes of acute myocarditis in children and adults and have been implicated in dilated cardiomyopathy. Although there is considerable information regarding the cellular immune response in viral heart disease, little is known about innate signaling mechanisms within the infected cardiac myocyte that contribute to host defense against viral infection. Studies from this and other laboratories have identified the presence of a family of innate immune receptors in the heart termed Toll-like receptors (TLRs). Importantly, recent studies have shown that TLR3 and TLR4 mediated signaling contributes to the induction of anti-viral cytokines through the adaptor molecule termed Toll-interleukin-1 receptor (TIR) domain-containing adaptor inducing interferon-¿ (TRIF). Our preliminary data in mice deficient in TLR3, TLR4 or TRIF show that the TLR3/4?TRIF signaling pathway is essential for the control of early viral replication, as well as the optimal induction of an anti-viral response in the heart. Based upon the foregoing observations the immediate specific objectives of this proposal will be to test the following hypotheses: (1) Signaling through TLR3 and TLR4 induces an anti-viral response in the hearts of enterovirus infected mice through a TRIF-dependent pathway, and (2) TRIF amplification of the antiviral response protects the heart against cytopathic injury, left ventricular dilatation and loss of myocardial contractility. Four Aims are envisioned. In Specific Aim 1 we will test the hypothesis that induction of the innate antiviral response in the heart following enteroviral infection is mediated by TLR3 and TLR4 via a TRIF-dependent pathway. Specific Aim 2 will test the hypothesis that loss of TLR3/TLR4?TRIF signaling will result in increased virus-induced cytopathic injury in the heart, leading to left ventricular dilatation and loss of myocardial contractility. Specific Aim 3 will test the hypothesis that overexpression of TRIF will protect cardiac myocytes from virus-induced cytopathic injury, augment the innate anti-viral response in the heart, and prevent the development of left ventricular dilatation and loss of myocardial contractility associated with an enteroviral infection. Specific Aim 4 will test the hypothesis that the TRIF mediated cardiac cytoprotection results from the ability of the N-terminal and C-terminal regions of TRIF to activate distinct antiviral mechanisms. Thus, the proposed studies should provide definitive new information regarding the mechanisms of activation, as well as the role of the innate immune system (TLRs) in viral heart disease. PUBLIC HEALTH RELEVANCE: Viral infection of the heart may cause severe heart failure and death in children and adults. There is no specific treatment for this disease and patients may eventually require heart transplantation. The studies proposed in this grant will give us a better understanding of the disease and may lead to improved treatment options.

描述（由适用提供）：心脏的病毒感染是儿童和成人急性心肌炎最常见的原因，并且已在扩张的心肌病中实施。尽管有关病毒心脏病中细胞免疫响应的大量信息，但对于感染的心肌细胞中的先天信号传导机制知之甚少，这有助于宿主防御病毒感染。来自该实验室和其他实验室的研究确定了心脏中的先天免疫受体家族称为收费受体（TLR）。重要的是，最近的研究表明，TLR3和TLR4介导的信号传导通过称为Toll-Interleukin-1受体1受托型型型衔接子衔接子诱导的干扰素的辅助分子（TRIF）促进抗病毒细胞因子诱导抗病毒细胞因子。我们在TLR3，TLR4或TRIF中特异的小鼠中的初步数据表明，TLR3/4？TRIF信号通路对于控制早期病毒复制以及心脏中抗病毒反应的最佳诱导至关重要。基于上述观察结果，该提案的直接特定目标将是测试以下假设：（1）通过TLR3和TLR4发出信号传导在肠内感染小鼠的心脏中引起抗病毒反应，并通过TRIF依赖性途径和抗病毒反应的抗病毒疗法的损失，（2）2）（2）2）（2）2）（2）避免疾病的疾病，（2）2）心肌收缩。设想了四个目标。在特定的目标1中，我们将测试以下假设：肠病毒感染后，肠病毒感染后心脏先天抗病毒反应的诱导是由TLR3和TLR4通过TRIF依赖性途径介导的。具体目标2将检验以下假设：TLR3/TLR4？TRIF信号的丧失会导致病毒诱导的心脏损伤增加，导致左心室扩张和心肌收缩性丧失。具体目标3将检验以下假设：TRIF的过表达将保护心肌细胞免受病毒诱导的细胞损伤，增强心脏中先天抗病毒反应，并防止左心室扩张和与肠球病毒感染相关的心肌收缩性的丧失。具体目标4将检验以下假设：TRIF介导的心脏细胞保护作用是由TRIF的N末端和C末端区域激活不同抗病毒机制的能力。这是拟议的研究应提供有关激活机制以及先天免疫系统（TLR）在病毒心脏病中的作用的明确新信息。公共卫生相关性：心脏的病毒感染可能导致儿童和成人的严重心力衰竭和死亡。没有针对这种疾病的特定治疗方法，患者最终可能需要心脏移植。该赠款中提出的研究将使我们对疾病有更好的了解，并可能导致改善治疗方案。