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.