Neuroendocrine control of TLR4-dependent inflammation in influenza

流感中 TLR4 依赖性炎症的神经内分泌控制

基本信息

批准号：
10397534
负责人：
Kari Ann Shirey
金额：
$ 17.95万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-05-01 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10397534
关键词：
2019-nCoV Acute Lung Injury Acute Respiratory Distress Syndrome Acute respiratory infection Affect Agonist American Animal Model Antiviral Agents Bacterial Infections Biological Markers Blood Circulation Bombesin Receptor Cell Death Cells Centers for Disease Control and Prevention (U.S.)Cessation of life Chromatin Clinical Cotton Rats Cytokine Gene Data Disease Disease Outbreaks Epithelial Cells Experimental Models GRP gene Gastrin releasing peptide Gene Expression Generations Goals HMGB1 Protein Histopathology Human ICAM1 gene Immune Immune response Immunity Infection Infiltration Inflammation Inflammatory Response Influenza Influenza A Virus, H1N1 Subtype Innate Immune Response Lead Lipopolysaccharides Lung Measures Mediating Mediator of activation protein Messenger RNA Metabolic stress Molecular Morbidity - disease rate Mus Neurons Neurosecretory Systems Oxidative Stress Pathology Pathway interactions Patients Pattern Pattern recognition receptor Play Process Production Proteins Publishing Pulmonary Inflammation Pulmonary Pathology Reagent Regulation Reporting Resistance Rodent Model Role Secondary to Sepsis Serum Severity of illness Sigmodon Signal Pathway Signal Transduction Streptococcus pneumoniae Symptoms TLR4 gene Techniques Testing Therapeutic Vaccination Vaccines Virus Virus Replication age group airway epithelium antagonist anti-viral efficacy base cytokine cytokine release syndrome gamma-Aminobutyric Acid gastrin inhibitor global health human disease influenza infection influenza virus strain influenzavirus inhibitor macrophage methicillin resistant Staphylococcus aureus monocyte mortality mouse model mouse toll-like receptor 4 novel strategies novel therapeutics pandemic disease pathogen pediatric patients protein expression receptor receptor expression respiratory respiratory pathogen respiratory virus response secondary infection signal recognition particle receptor systemic inflammatory response targeted biomarker therapeutic target universal influenza vaccine

项目摘要

SUMMARY Influenza is a highly contagious respiratory illness that the CDC has estimated to afflict ~47.5 million Americans with up to 62,00 deaths from October 1, 2019 to April 4, 2020. In the absence of a “universal influenza vaccine,” yearly vaccination is strongly recommended; however, the composition of each vaccine is based on predictions of which strains will predominate in the following year and such predictions may be incorrect. Approved antivirals can ameliorate disease by limiting viral replication, but they must be administered early in infection to be effective, and resistant influenza strains have emerged. While influenza-induced disease is initiated by viral replication resulting in airway epithelial damage, the severe inflammatory response that follows as a result of metabolic stress in innate immune cells (e.g., macrophages) ultimately elicits a “cytokine storm” that may lead to acute respiratory distress syndrome (ARDS) and death. Thus, a new approach that targets the host innate immune response would represent a highly significant therapeutic advance for influenza as well as other respiratory viruses that lead to ARDS, e.g., SARS-CoV-2. We have identified Toll-like receptor 4 (TLR4), a pattern recognition receptor best known for its ability to sense Gram-negative lipopolysaccharide (LPS), as key to the host inflammatory response to influenza. This was initially surprising since influenza virus does not express any “pathogen-associated molecular patterns” that trigger inflammation via TLR4. Nonetheless, using both TLR4-/- mice and multiple TLR4 antagonists in both a mouse model of influenza infection, as well as in cotton rats (Sigmodon hispidus; CR) that are susceptible to non-adapted strains of human influenza, we rigorously demonstrated that TLR4 signaling is central to the generation of lung and systemic inflammation in response to infection. We identified a host-derived protein, High Mobility Group Box-1 (HMGB1), released from dying cells during infection, that acts as a “danger-associated molecular pattern,” thereby triggering TLR4 through its co-receptor, MD2. Recently, we identified a second host-derived protein, gastrin-releasing peptide (GRP), as contributory to influenza-mediated disease, using three distinct inhibitors of GRP or GRP receptor signaling to significantly blunt cytokine production, lung pathology, and lethality when administered to mice therapeutically. Our published and preliminary data support the central hypothesis that these two mediators are interrelated and converge during the host response to influenza infection. In two Specific Aims, we propose to (1) delineate influenza-mediated interactions between GRP receptor (GRPR)- and TLR4/MD2-mediated signaling, and (2) correlate GRP and HMGB1 levels with disease severity in two distinct experimental models of influenza-induced disease and in influenza-infected patients. In this exploratory R21 application, we shall seek to identify the mechanistic underpinnings of the relationship between these two signaling pathways with the potential of identifying therapeutic strategies to ameliorate disease.

概括流感是一种高度传染性的呼吸道疾病从2019年10月1日到2020年4月4日，美国人有62,00人死亡。影响力疫苗，“强烈建议每年疫苗；但是，每种疫苗的组成是基于对第二年菌株将占主导地位的预测，此类预测可能是不正确。批准的抗病毒药可以通过限制病毒复制来改善疾病，但必须给予它们在感染的早期，有效，并且有抵抗力的影响者出现了。而影响者引起的疾病是通过病毒复制引发的，导致气道上皮损害，这是严重的炎症反应遵循先天免疫细胞中的代谢应激（例如巨噬细胞）最终引起“细胞因子风暴”可能导致急性呼吸窘迫综合征（ARDS）和死亡。这是一种新方法目标宿主先天免疫反应将代表影响力的高度显着的热疗法以及导致ARDS的其他呼吸道病毒，例如SARS-COV-2。我们已经确定了类似收费的接收器 4（TLR4），一种模式识别受体，以其感知革兰氏阴性脂多糖的能力而闻名（LPS），作为宿主对影响力的炎症反应的关键。最初这是令人惊讶的，因为影响力病毒不表达通过TLR4触发注射的任何“病原体相关的分子模式”。尽管如此，在两种小鼠的影响力模型中都使用TLR4 - / - 小鼠和多个TLR4拮抗剂感染，以及在棉花大鼠（西格莫登·西皮斯；人类影响力，我们严格地证明TLR4信号传导是肺和产生的核心响应感染的系统性炎症。我们确定了宿主衍生的蛋白质，高移动性组框1 （HMGB1）在感染过程中从垂死细胞中释放出来，它是“危险相关的分子模式”，从而通过其共受体MD2触发TLR4。最近，我们确定了第二个宿主衍生的蛋白质，使用三种不同的抑制剂，使用三种不同的抑制剂 GRP或GRP受体信号传导，以显着钝化细胞因子的产生，肺病理和致死性对小鼠理论进行管理。我们发布的初步数据支持了以下中心假设这两个介体在宿主对影响力感染的反应期间有相互关联并融合。一两个具体目的，我们建议（1）描述GRP受体（GRPR） - 和TLR4/MD2介导的信号传导，（2）将GRP和HMGB1水平与疾病的严重程度相关联。影响力诱导的疾病和受影响的患者的独特实验模型。在此探索性中 R21应用，我们将寻求确定这两者之间关系的机械基础信号通路具有鉴定治疗策略改善疾病的潜力。