Defining the role of mast cells during influenza A virus infection

定义肥大细胞在甲型流感病毒感染过程中的作用

• 批准号: 8028158
• 负责人: JOSHUA J OBAR
• 金额: $ 16.2万
• 依托单位: MONTANA STATE UNIVERSITY - BOZEMAN
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-02-15 至 2013-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8028158
• 关键词: Address; Age; Alveolar; Area; Bacterial Infections; Biological Assay; Bone Marrow; Bronchi; C-KIT Gene; Cells; Chimera organism; Chymase; Color; Data; Dendritic Cells; Detection; Disease Outbreaks; Disease Outcome; Environment; Enzyme-Linked Immunosorbent Assay; Epithelial Cells; Event; Faculty; Family; Flow Cytometry; Foundations; Frequencies; Future; Gastrointestinal tract structure; Genitourinary system; Hematopoiesis; Immune; Immune response; Infection; Inflammation; Inflammatory; Inflammatory Response; Influenza A Virus, H1N1 Subtype; Influenza A Virus, H5N1 Subtype; Influenza A virus; Institutes; Invaded; Knowledge; Lung; Mediating; Morbidity - disease rate; Mus; Mutation; Parasitic infection; Pathogenicity; Pathologic; Pathology; Pathway interactions; Peptide Hydrolases; Pharmacologic Substance; Plaque Assay; Play; Population; Primary Cell Cultures; Principal Investigator; Proteinase-Activated Receptors; Proto-Oncogene Protein c-kit; Public Health; Regulation; Research; Respiratory Tract Infections; Response Elements; Role; Running; Severities; Skin; Staging; System; Techniques; Testing; Time; Training; Tryptase; Universities; Viral; Virus Diseases; Work; cell type; chemokine; cytokine; experience; flexibility; immunopathology; interest; lung injury; mast cell; member; mortality; new therapeutic target; novel; pandemic disease; pathogen; professor; programs; reconstitution; respiratory; response; seasonal influenza; sound

DESCRIPTION (provided by applicant): Influenza A virus (IAV) and especially the highly pathogenic IAV strains, such as those causing the recent H5N1 and H1N1 outbreaks, represent a significant public health concern. These strains of IAV cause significantly greater morbidity and mortality than seasonal IAV strains. However, the exact cause of the increased morbidity and mortality remains controversial, with increased viral pathogenicity, increased immunopathology, and increase co-infections proposed as possible mechanisms. This proposal will examine the early host response elements to IAV infection, specifically examining the role that mast cells and protease- activated receptors play in regulating the morbidity and mortality associated with IAV infection. Mast cells could be critical in orchestrating the host response to respiratory infection with IAV, because they are found at elevated frequencies around the bronchi within the lungs. Furthermore, our preliminary data show that mast cell-deficient mice develop significantly less IAV-association morbidity. Therefore, we propose to determine how mast cells are activated during respiratory infection with IAV and what role they play in regulating disease outcome. Secondly, we will determine how mast cells are orchestrating the deleterious host inflammatory response following IAV infection. Specifically, mast cell activation of the protease-activated receptor family on alveolar epithelial cells will be explored, as well as the subsequent regulation of inflammatory chemokines and cytokines by both mast cells and the protease-activated receptor family. Our preliminary data support the hypothesis that mast cells and the protease-activated receptor family are important in regulating morbidity associated with respiratory IAV infection. Thus, by understanding these early events, we hope to identify novel pharmacological targets, which can be used to limit morbidity and mortality from IAV infection. As can be seen, the focus of this proposal is quite distinct from the previous research that I have conducted. However, I have been well trained in the experimental systems and techniques needed for the successful completion of the proposed studies. For example, I have gained extensive experimental experience in the use of mice for understanding the immune response to numerous viral pathogens, including IAV. In addition, I have gained substantial training in many of the techniques required for the successful completion of the proposed studies, which include multi-parameter flow cytometry (we are routinely conducting 12 parameter studies now), primary cell culture from bone marrow, Luminex" bead assays for the detection of multiple cytokines/chemokines at the same time, viral plaque assays, adoptive cellular transfers, and ELISA assays. Together, this previous experience provides a strong experimental foundation, which will allow me the flexibility to apply this knowledge and technical ability to a distinct area of study, therefore developing a new and independent research direction that addresses critical gaps in knowledge of immune regulation of viral infection as an Assistant Professor. Furthermore, my current and future research institutes provide me ample technical opportunities to conduct these studies, including access to a 10-color BD LSRII cytometer, a g-cell irradiator for making bone marrow chimeras, and BioPlex200 machine for running Luminex plates. Additionally, faculty members at both my current and future universities provide a sound network of knowledge which will be invaluable for the successfully completion of the proposed studies. Each year, influenza A virus infection leads to significant morbidity and mortality within certain groups, while periodic pandemic strains cause significantly greater morbidity and mortality throughout the entire population. What causes the significantly elevated rates of morbidity and mortality remains controversial. This proposal will examine the early events during the host response to influenza A virus infection and could elucidate potential novel therapeutic targets for limiting morbidity and mortality associated with influenza A virus infection.

描述（由申请人提供）：甲型流感病毒（IAV），特别是高致病性IAV毒株，如引起最近H5N1和H1N1疫情的毒株，是一个重大的公共卫生问题。这些病毒株的发病率和死亡率明显高于季节性病毒株。然而，发病率和死亡率增加的确切原因仍然存在争议，病毒致病性增加，免疫病理增加，合并感染增加被认为是可能的机制。本研究将研究IAV感染的早期宿主反应因素，特别是肥大细胞和蛋白酶激活受体在调节与IAV感染相关的发病率和死亡率中的作用。肥大细胞可能在协调宿主对IAV呼吸道感染的反应中起关键作用，因为它们在肺部支气管周围的频率较高。此外，我们的初步数据显示肥大细胞缺陷小鼠的iav相关发病率显著降低。因此，我们建议确定在IAV呼吸道感染期间肥大细胞是如何被激活的，以及它们在调节疾病结局中起什么作用。其次，我们将确定肥大细胞如何在IAV感染后协调有害的宿主炎症反应。具体来说，将探讨蛋白酶激活受体家族在肺泡上皮细胞上的肥大细胞活化，以及肥大细胞和蛋白酶激活受体家族随后对炎症趋化因子和细胞因子的调节。我们的初步数据支持肥大细胞和蛋白酶激活受体家族在调节呼吸道IAV感染相关发病率中起重要作用的假设。因此，通过了解这些早期事件，我们希望确定新的药理学靶点，这些靶点可用于限制IAV感染的发病率和死亡率。