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Pulmonary Epithelial Dynamics and Innate Host Defense

肺上皮动力学和先天宿主防御

基本信息

批准号：
10063952
负责人：
Francis Xavier McCormack
金额：
$ 48.1万
依托单位：
UNIVERSITY OF CINCINNATI
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-12-07 至 2022-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10063952
关键词：
Adrenal Cortex Hormones Affect Air Sacs Alveolar Alveolitis Alveolus Apoptosis Apoptotic BRAF gene Binding Bronchiolitis Bronchitis Cell Cycle Cell Proliferation Cell model Cell surface Cells Centers for Disease Control and Prevention (U.S.)Cessation of life Chronic Clinical Cough Headaches Coughing Cytoplasm Data Development Dose Elderly Endocytosis Epidemic Epithelial Epithelial Cells Event FRAP1 gene Fever Fibroblast Growth Factor Receptors Genes Genetic Models Goals Host Defense Human Hyperoxia Immune In Vitro Incidence Infection Influenza Influenza A Virus, H1N1 Subtype Influenza A virus Inhalation Integration Host Factors Ligand Binding Lung MAP Kinase Gene MAPK Signaling Pathway Pathway MEKs Membrane Glycoproteins Mitogens Modeling Mouse Cell Line Mus Myalgia Natural Resistance PI3K/AKT Pathway interactions Play Pneumonia Pre-Clinical Model Predisposition Process Production Prophylactic treatment Proteins Pulmonary Heart Disease RNA Viruses Randomized Controlled Trials Receptor Protein-Tyrosine Kinases Recovery Resistance Resistance to infection Role Severities Sialic Acids Signal Transduction Sirolimus Stimulus Syndrome Tamoxifen Testing Therapeutic Tracheitis Tube Viral Virus Virus Diseases Virus Replication alveolar epithelium alveolar type II cell in vivo influenza infection influenza pneumonia influenzavirus inhibitor/antagonist keratinocyte growth factor lung injury mTOR Inhibitor mortality novel novel strategies prenatal cigarette smoking resistance mechanism sialic acid receptor

项目摘要

Project Summary The RNA virus that causes influenza is inhaled into the airways and binds to terminal sialic acid residues on host cell surface glycoproteins via viral sialic acid receptors. The tracheitis, bronchitis and bronchiolitis that results is often accompanied by incapacitating cough, headache, fever and myalgias, but the syndrome usually resolves in 7-10 days without development of alveolitis. This is fortunate because once the pulmonary parenchyma is involved, mortality increases almost 60 fold, from 0.3 to 17.8 annual deaths per 100,000(2006 CDC data). Because we believe that infection of alveolar type II (ATII) cells is the pivotal event in the conversion of a self-limited influenza virus (IV) airway infection to a potentially lethal alveolar infection, our proposal focuses on the mechanisms that render the ATII cells resistant or susceptible to infection with IV. Although ATII cells are clearly the primary epithelial target for IV in the alveolus, they are remarkably resistant to IV infection in their typically quiescent state in the unperturbed lung, in which fewer than 1% of ATII cells are cycling. Recent in vitro studies have demonstrated that the PI3K/Akt/mTOR pathway, which regulates cellular proliferation, plays a key role in susceptibility and severity of IV infection by enhancing cell surface binding, endocytosis, lysosomal acidification driven entry into the cytoplasm, replication using cellular translational machinery, and anti-apoptotic mechanisms that prolong viral production. Mitogenic stimulation of PI3K/Akt/mTOR pathway with intrapulmonary keratinocyte growth factor (KGF) converts ATII cells from a quiescent, IV resistant state to a proliferative, IV susceptible state, and hastens the progression of IV infection from the conducting airways to the alveolus, markedly accelerating mortality. Our hypothesis is that key host factors, such as transient hyperoxia, render hosts susceptible to influenza pneumonia (IP) through their impact on the proliferative tone of the ATII pool. Our goals are to determine the mechanisms of mitogen-induced susceptibility to influenza A virus susceptibility by completing three specific aims: 1) mechanisms of mitogen- induced susceptibility of AECII cells to IAV infection, 2) host states that affect IAV susceptibility through mitogenic effects on AECII cells, 3) genetic models of AECII signaling and anti-proliferative strategies for IAV prophylaxis and therapy. Successful completion of these aims will reveal the importance of a paradigm-shifting, AECII-centric host susceptibility mechanism, and suggest novel approaches to influenza prophylaxis and therapy.

项目概要引起流感的RNA病毒被吸入呼吸道并与呼吸道末端唾液酸残基结合。通过病毒唾液酸受体作用于宿主细胞表面糖蛋白。气管炎、支气管炎和细支气管炎结果常常伴有咳嗽、头痛、发烧和肌痛，但该综合征通常 7-10 天内消退，不会出现肺泡炎。这是幸运的，因为一旦肺部涉及实质组织，死亡率增加近 60 倍，从每年每 10 万人死亡 0.3 人增加到 17.8 人（2006 年）疾病预防控制中心数据）。因为我们相信 II 型肺泡 (ATII) 细胞的感染是整个过程的关键事件。自限性流感病毒（IV）气道感染转化为潜在致命的肺泡感染，我们的该提案的重点是使 ATII 细胞对 IV 感染具有抵抗力或易感性的机制。尽管 ATII 细胞显然是肺泡内 IV 的主要上皮靶标，但它们具有显着的耐药性在未受干扰的肺部中，IV 感染处于典型的静止状态，其中只有不到 1% 的 ATII 细胞骑自行车。最近的体外研究表明，PI3K/Akt/mTOR 通路可调节细胞增殖，通过增强细胞表面结合，在 IV 感染的易感性和严重程度中发挥关键作用，内吞作用，溶酶体酸化驱动进入细胞质，使用细胞翻译复制延长病毒生产的机械和抗凋亡机制。有丝分裂刺激 PI3K/Akt/mTOR 通路与肺内角质形成细胞生长因子 (KGF) 将 ATII 细胞从静态、IV 抵抗状态转变为增殖、IV 易感状态，并加速 IV 感染的进展从传导气道到肺泡，显着加速死亡率。我们的假设是关键宿主暂时性高氧等因素通过其影响使宿主易患流感肺炎 (IP) ATII池的增殖基调。我们的目标是确定丝裂原诱导的机制通过完成三个具体目标来评估对甲型流感病毒的易感性：1）丝裂原的机制诱导 AECII 细胞对 IAV 感染的易感性，2) 宿主状态通过影响 IAV 易感性对 AECII 细胞的促有丝分裂作用，3) AECII 信号传导的遗传模型和 IAV 的抗增殖策略预防和治疗。成功完成这些目标将揭示范式转变的重要性，以 AECII 为中心的宿主易感性机制，并提出流感预防和治疗的新方法治疗。