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

• 批准号: 9123926
• 负责人: JOSHUA J OBAR
• 金额: $ 40.5万
• 依托单位: DARTMOUTH COLLEGE
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-06-01 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9123926
• 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; Health; 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; Viral Respiratory Tract Infection; 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; receptor; respiratory; response; seasonal influenza; targeted treatment

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。甲型流感病毒（IAV）是季节性病毒性呼吸道感染的主要原因。IAV引起的疾病不仅具有显著的经济影响，而且仅在美国每年就有约36，000人死亡和约170万人住院治疗。此外，IAV有可能导致全球性大流行，其发病率和死亡率显著增加。与IAV感染相关的发病率和死亡率被认为是重要的免疫病理学的结果。IAV毒株诱导的肺部疾病的严重程度各不相同，这是明确的。因此，我们实验室的长期目标是了解对IAV感染的免疫反应所引起的保护和宿主损害之间的微妙平衡。肺中抵抗病原体的最初防线包括肺泡上皮细胞、内皮细胞、组织驻留肺泡巨噬细胞、树突状细胞和肥大细胞。然而，肥大细胞在呼吸道病毒感染中的作用一直未被研究。重要的是，我们的数据表明，肥大细胞是至关重要的启动流感病毒诱导的炎性免疫病理学在病毒株特异性的方式，然而，肥大细胞没有发挥关键作用，在清除IAV从呼吸道。此外，委员会认为， 其他人已经报道，在人感染IAV期间，可以检测到组胺水平显著升高，与IAV诱导的症状同时发生。因此，肥大细胞可能参与了对IAV感染的免疫应答，但其作用尚未阐明。该提案有三个具体目标，将测试肥大细胞在IAV中的作用。 感染，并阐明负责其激活，招募和活动的分子机制。在具体的目标1中，我们将确定哪些受体调节肥大细胞的活性，以响应IAV，并确定新招募的肥大细胞祖细胞在IAV诱导的肺部炎症的作用。在具体目标2中，我们将定义在呼吸道IAV感染期间诱导炎症诱导的肺损伤的关键肥大细胞效应物。在具体目标3中，我们将定义IAV血凝素在启动肥大细胞依赖性IAV免疫应答中的作用。这三个目标的实现将为呼吸道病毒感染时肥大细胞激活和功能的机制提供新的见解。总之，了解肥大细胞和IAV株特异性对炎症反应的贡献不仅在开发和适当使用新型宿主靶向治疗剂以限制IAV诱导的宿主损伤和发病率方面至关重要，而且还将提供新型抗病毒治疗剂可以靶向的病毒蛋白质的新区域。