Mast cell dependent inflammatory cascade during influenza A virus infection

甲型流感病毒感染期间肥大细胞依赖性炎症级联反应

基本信息

批准号：
8853792
负责人：
JOSHUA J OBAR
金额：
$ 8.5万
依托单位：
MONTANA STATE UNIVERSITY - BOZEMAN
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-06-01 至 2015-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8853792
关键词：
Acute Lung Injury Address Alveolar Alveolar Macrophages Anti-Inflammatory Agents Anti-inflammatory Bacterial Infections Binding Biochemical CCL3 gene CCL4 gene CXCL2 gene Cells Cessation of life Characteristics Clinical Cromoglicic Acid Data Dendritic Cells Development Disease Endothelial Cells Epithelial Cells Equilibrium Event Generations Goals Histamine Hospitalization Human Immune Immune response Immune system Immunologic Receptors Infection Inflammation Inflammatory Inflammatory Response Influenza Influenza A virus Injury Knowledge Laboratories Lead Lung Lung Inflammation Lung diseases Mast Cell Stabilizer Mediating Methods Molecular Molecular Structure Morbidity - disease rate Pathology Pathway interactions Pattern recognition receptor Play Population Proteins Quercetin Recruitment Activity Reporting Respiratory System Respiratory Tract Infections Respiratory tract structure Role Secondary to Severities Sialic Acids Source Specificity Sphingosine-1-Phosphate Receptor Symptoms Targeted Research Testing The Sun Therapeutic Tissues Tropism United States Vaccines Viral Viral Hemagglutinins Viral Proteins Virus Virus Diseases chemokine cytokine design economic impact follow-up immunopathology influenzavirus insight lung injury mast cell mortality new therapeutic target novel pandemic disease pandemic influenza pathogen progenitor public health relevance receptor respiratory response seasonal influenza therapeutic target

项目摘要

DESCRIPTION (provided by applicant): The respiratory tract is a major portal of entry for many pathogens. Influenza A virus (IAV) is a major cause of seasonal viral respiratory infections. Not only do IAV-induced illnesses have a significant economic impact, but there are also ~36,000 deaths and ~1.7 million hospitalizations each year in the United States alone. Moreover, IAV has the potential to cause global pandemics, which have significantly greater morbidity and mortality. Morbidity and mortality associated with IAV infections is thought be the result of significant immunopathology. It is well defined that IAV strains vary in the severity of lung disease they induce. Thus, the long-term goal of our laboratory is to understand the fine balance between protection and host damage caused by immune responses to IAV infection. The initial lines of defense against pathogens in the lungs include alveolar epithelial cells, endothelial cells, tissue resident alveolar macrophages, dendritic cells, and mast cells. However, the role of the mast cell has been under explored during respiratory viral infection. Importantly, our data demonstrate that mast cells are critical for initiating the inflammatory immunopathology induced by influenza virus in a virus strain-specific manner; however, mast cells did not play a critical role in the clearance of IAV from the respiratory tract. Furthermore, others have reported that during IAV infection of humans significantly elevated levels of histamine can be detected coincident with IAV induced symptoms. Thus, mast cells are likely to participate in the immune response to IAV infection, but what their role is has not been elucidated. This proposal has three specific aims which will test the role of mast cells during IAV infection and elucidate the molecular mechanisms responsible for their activation, recruitment, and activity. In specific aim 1, we will identify which receptors modulate mast cell activity in response to IAV and determine the role of newly recruited mast cell progenitors in the IAV-induced lung inflammation. In specific aim 2, we will define the key mast cell effectors that are critical for inducing the inflammation- induced pulmonary injury during respiratory IAV infection. In specific aim 3, we will define the role of the IAV hemaggultinin in initiating the mast cell-dependent IAV immune response. Completion of these three aims will offer novel insights into the mechanisms of mast cell activation and function during respiratory viral infection. In conclusion, understanding mast cells and IAV strain specificity contributions to the inflammatory response will not only be crucial in the development and appropriate use of novel host-targeted therapeutics to limit IAV-induced host damage and morbidity, but will also provide novel regions of viral proteins which could be targeted by novel anti-viral therapeutics.

描述（由申请人提供）：呼吸道是许多病原体的主要入口门户。流感病毒（IAV）是季节性病毒呼吸道感染的主要原因。 IAV诱导的疾病不仅具有重大的经济影响，而且每年在美国，每年也有约170万例住院。此外，IAV有可能引起全球大流行，这些大流行病的发病率和死亡率明显更高。与IAV感染相关的发病率和死亡率被认为是显着免疫病理学的结果。很好的定义是，IAV菌株在它们诱导的肺部疾病的严重程度上有所不同。因此，我们实验室的长期目标是了解由IAV感染的免疫反应引起的保护与宿主损害之间的良好平衡。针对肺中病原体的最初防御线包括肺泡上皮细胞，内皮细胞，组织驻留的肺泡巨噬细胞，树突状细胞和肥大细胞。然而，在呼吸道病毒感染期间，肥大细胞的作用一直在探讨。重要的是，我们的数据表明，肥大细胞对于以病毒特异性方式引起流感病毒引起的炎症免疫病理至关重要。然而，肥大细胞在从呼吸道清除IAV中起关键作用。此外，其他人则报告说，在人类IAV感染期间，可以检测到与IAV诱发症状相一致的组胺水平升高。因此，肥大细胞可能会参与对IAV感染的免疫反应，但尚未阐明其作用。该提案具有三个特定的目标，可以测试肥大细胞在IAV中的作用感染并阐明了负责其激活，募集和活性的分子机制。在特定目标1中，我们将确定哪些受体对IAV的响应调节肥大细胞活性，并确定新募集的肥大细胞祖细胞在IAV诱导的肺部炎症中的作用。在特定目标2中，我们将定义关键的肥大细胞效应子，这些肥大细胞效应对于在呼吸IAV感染过程中诱导炎症引起的肺损伤至关重要。在特定的目标3中，我们将定义IAV血凝素在启动肥大细胞依赖性IAV免疫反应中的作用。这三个目标的完成将提供有关培训病毒感染过程中肥大细胞激活和功能机制的新见解。总之，了解肥大细胞和IAV菌株特异性对炎症反应的贡献不仅对开发和适当使用新型宿主靶向的疗法至关重要，以限制IAV诱导的宿主损伤和发病率，而且还将提供新型病毒蛋白的新型区域，这些区域可由新型的抗病毒疗法靶向。