Pulmonary Epithelial Dynamics and Innate Host Defense

项目摘要 引起流感的RNA病毒被吸入呼吸道，并与呼吸道上的末端唾液酸残基结合， 宿主细胞表面糖蛋白通过病毒唾液酸受体。气管炎、支气管炎和细支气管炎， 结果常伴有失能性咳嗽、头痛、发热和肌痛，但该综合征通常 在7-10天内消退，不发生肺泡炎。这是幸运的，因为一旦肺部 当软组织受累时，死亡率几乎增加60倍，从每年每100，000例死亡0.3例增加到17.8例（2006年 CDC数据）。因为我们相信肺泡II型（ATII）细胞的感染是肺内炎症的关键事件， 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 该提案的重点是使ATII细胞对IV感染具有抗性或易感性的机制。 虽然ATII细胞显然是肺泡中IV的主要上皮靶，但它们具有显著的抵抗性。 IV感染在未受干扰的肺中处于典型的静止状态，其中少于1%的ATII细胞被 骑自行车最近的体外研究表明，调节细胞凋亡的PI 3 K/Akt/mTOR通路， 增殖，通过增强细胞表面结合在IV感染的易感性和严重性中起关键作用， 内吞作用，溶酶体酸化驱动进入细胞质，使用细胞翻译的复制 机制和延长病毒生产的抗凋亡机制。促有丝分裂刺激 PI 3 K/Akt/mTOR通路与肺内角质形成细胞生长因子（KGF）将ATII细胞从一个细胞因子转化为另一个细胞因子。 从静止的IV耐药状态转变为增殖的IV敏感状态，并加速IV感染的进展 从传导气道到肺泡，显著加速死亡率。我们的假设是关键宿主 短暂性高氧等因素通过其影响使宿主易患流感肺炎（IP ATII池的增殖性音调。我们的目标是确定有丝分裂原诱导的 通过完成三个具体目标来提高对甲型流感病毒易感性的易感性：1）促分裂原的机制， 诱导AECII细胞对IAV感染的易感性，2）通过以下途径影响IAV易感性的宿主状态： 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。这些目标的成功实现将揭示范式转变的重要性， AECII为中心的宿主易感性机制，并提出新的方法来预防流感， 疗法

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.