Polymicrobial Interactions in the Lung

铜绿假单胞菌是一种条件致病菌，也是慢性阻塞性肺疾病患者的重要致病菌。 阻塞性肺疾病(COPD)、社区获得性肺炎(CAP)、呼吸机相关 肺炎(VAP)、非纤维性支气管扩张和囊性纤维化(CF)。最近的研究表明，病毒和P. 肺部的铜绿假单胞菌感染是协同作用的，并极大地增加了发病率和死亡率。 与慢性阻塞性肺疾病、呼吸机相关性肺炎和非慢性阻塞性肺疾病相关。我研究的长期目标是 阐明铜绿假单胞菌和呼吸道病毒协同作用的细胞和分子机制 导致肺部疾病。我的短期研究目标是阐明铜绿假单胞菌 感染干扰了宿主对呼吸道病毒的清除。铜绿假单胞菌分泌一种名为Cif(CFTR)的蛋白质 抑制因子，最初命名是因为它能够抑制CFTR介导的呼吸道细胞氯的分泌)， 该基因由PA2934(或cif)基因编码。CIF是由P。 铜绿假单胞菌通过下调CFTRCl分泌和粘液纤毛抑制宿主免疫反应 通行证。此外，Cif还减少了TAP1(与抗原处理相关的转运蛋白)的丰度， 我最近的初步研究表明，它抑制了由I类MHC呈递的甲型流感病毒抗原 分子和细胞毒性T淋巴细胞(CTL)清除病毒感染的能力。我的初步数据也 证明细胞因子，即干扰素，由宿主释放，以回应病毒病原体，增加 铜绿假单胞菌Cif的分泌。关于分泌的细菌蛋白如何抑制细菌的 宿主对病毒病原体的免疫反应，而关于宿主如何免疫的数据很少。 反应改变了微生物病原体释放细菌毒素的方式。因此，我将在体外使用 生化、高分辨率成像和体内免疫学技术检测以下四种特异性 这个建议的目的是：(1)检验CIF减少抗原提呈和CTL介导的假设 清除；(2)检验CIF减少流感病毒抗原提呈和CTL介导的假设 清除；(3)检验铜绿假单胞菌和呼吸道合胞病毒混合感染使每个病原体受益的假设 减少呼吸道合胞病毒的病毒抗原呈递和CTL清除，并促进铜绿假单胞菌的定植；以及 (4)检验宿主免疫应答增加铜绿假单胞菌毒力因子分泌的假说。我 预期这些研究将阐明铜绿假单胞菌如何降低肺部清除病毒的能力 感染，并最终确定新的治疗方法来控制铜绿假单胞菌和 呼吸道病毒感染。

Pseudomonas aeruginosa is an opportunistic pathogen and an important pathogen in patients with chronic obstructive pulmonary disorder (COPD), community acquired pneumonia (CAP), ventilator-associated pneumonia (VAP), non-CF bronchiectasis and cystic fibrosis (CF). Recent studies suggest that viral and P. aeruginosa infections of the lung are synergistic and dramatically contribute to the morbidity and mortality associated with COPD, CF, CAP, VAP, and non-CF bronchiectasis. The long-term goal of my research is to elucidate the cellular and molecular mechanisms whereby P. aeruginosa and respiratory viruses synergize to cause lung disease. My short-term research goal is to elucidate the mechanism whereby P. aeruginosa infection interferes with host clearance of respiratory virus. P. aeruginosa secretes a protein called Cif (CFTR Inhibitory Factor, originally named because of its ability to inhibit CFTR-mediated Cl secretion by airway cells), which is coded by the PA2934 (or cif) gene. Cif, which is secreted by laboratory and clinical isolates of P. aeruginosa, inhibits the host immune response by down-regulating CFTR Cl secretion and mucociliary clearance. In addition, Cif reduces the abundance of TAP1 (Transporter Associated with Antigen Processing), which my recent preliminary studies reveal, suppresses influenza A virus antigen presentation by class I MHC molecules and the ability of cytotoxic T lymphocytes (CTL) to clear viral infections. My preliminary data also demonstrate that cytokines, namely interferon-γ, released by the host in response to viral pathogens, increase the secretion of Cif from P. aeruginosa. Very little is known about how secreted bacterial proteins suppress the host immune response to viral pathogens, and there is minimal data elucidating how the host immune response alters the release of bacterial toxins from microbial pathogens. Accordingly, I will use in vitro biochemical, high resolution imaging, and in vivo immunological techniques to test the following four specific aims in this proposal: (1) Test the hypothesis that Cif reduces antigen presentation and CTL-mediated clearance; (2) Test the hypothesis that Cif reduces influenza virus antigen presentation and CTL-mediated clearance; (3) Test the hypothesis that P. aeruginosa and RSV co-infection benefits each pathogen by reducing viral antigen presentation and CTL-clearance of RSV and promoting P. aeruginosa colonization; and (4) Test the hypothesis that the host immune response increases virulence factor secretion by P. aeruginosa. I anticipate that these studies will elucidate how P. aeruginosa reduces the ability of the lung to clear viral infections and, ultimately, identify new therapeutic approaches to control combined P. aeruginosa and respiratory virus infections.