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：
10193411
负责人：
Kari Ann Shirey
金额：
$ 23.18万
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 2023-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10193411
关键词：
2019-nCoV Acute Lung Injury Acute respiratory infection Adult Respiratory Distress Syndrome 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 Lung Inflammation 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 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 anti-viral efficacy base c new cytokine cytokine release syndrome gamma-Aminobutyric Acid gastrin inhibitor global health human disease influenza infection influenza virus strain influenzavirus inhibitor/antagonist 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，美国疾病控制与预防中心 (CDC) 估计会影响约 4750 万人从2019年10月1日到2020年4月4日，美国有多达62,00人死亡。在没有“普遍”的情况下流感疫苗”，强烈建议每年接种一次疫苗，但是每种疫苗的成分是不同的；基于对来年哪些菌株将占主导地位的预测，并且此类预测可能是批准的抗病毒药物可以通过限制病毒复制来改善疾病，但必须服用它们。在感染初期就有效，并且耐药流感病毒株已经出现，同时流感引起的疾病。由病毒复制引发，导致气道上皮损伤，严重的炎症反应由于先天免疫细胞（例如巨噬细胞）的代谢应激最终引发“细胞因子风暴”可能会导致急性呼吸窘迫综合征（ARDS）和死亡。靶向宿主先天免疫反应将代表流感治疗的一个非常重要的进步以及其他导致 ARDS 的呼吸道病毒，例如 SARS-CoV-2，我们已经鉴定出 Toll 样受体。 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)，最初是宿主对流感炎症反应的关键，自从流感病毒出现以来，这一点令人惊讶。不表达任何通过 TLR4 引发炎症的“病原体相关分子模式”。尽管如此，在流感小鼠模型中同时使用 TLR4-/- 小鼠和多种 TLR4 拮抗剂感染，以及对非适应性菌株敏感的棉鼠（Sigmodon hispidus；CR）在人类流感中，我们严格证明了 TLR4 信号传导对于肺和流感病毒的产生至关重要。我们鉴定了一种宿主衍生蛋白 High Mobility Group Box-1。（HMGB1），在感染过程中从垂死的细胞中释放出来，充当“与危险相关的分子模式”，最近，我们鉴定了第二种源自宿主的蛋白质，胃泌素释放肽（GRP），作为流感介导的疾病的贡献者，使用三种不同的抑制剂 GRP 或 GRP 受体信号传导显着减弱细胞因子的产生、肺部病理学和致死率我们发表的初步数据支持了以下中心假设：这两种介质在宿主对流感感染的反应过程中相互关联并聚合。具体目标，我们建议 (1) 描述流感介导的 GRP 受体 (GRPR) 之间的相互作用 - 和 TLR4/MD2 介导的信号传导，以及 (2) 将 GRP 和 HMGB1 水平与两种疾病的严重程度相关联流感引起的疾病和流感感染患者的不同实验模型。 R21 应用程序中，我们将寻求确定这两者之间关系的机械基础信号通路有可能确定改善疾病的治疗策略。