Alcorn Pilot

摘要 囊性纤维化(CF)是一种遗传性疾病，影响着美国和世界各地的数千人。损失 氯离子通道CF跨膜电导调节器(CFTR)的功能突变导致 呼吸道表面液体维持异常，粘液纤毛清除丧失。Cf患者患有 肺部慢性细菌感染，治疗资源有限。金黄色葡萄球菌是一种重要的 肺炎克雷伯菌中的革兰氏阳性菌随着耐甲氧西林金黄色葡萄球菌的流行 (MRSA)，这种细菌在不久的将来可能会在CF的发病机制中发挥更大的作用。耐甲氧西林金黄色葡萄球菌定植 与CF患者肺功能的更大下降有关，并可能经常发生流感多菌感染 在这种疾病中发现的。我们的实验室以前已经证明了17型免疫在 规范金黄色葡萄球菌的宿主防御。17型细胞因子IL-17和IL-22刺激抗菌肽 上皮细胞产生对金黄色葡萄球菌清除至关重要的物质。目前还不清楚是17型还是 相关的抗微生物反应在CF的背景下是异常的。此外，先前的病毒感染增加 通过抑制抗菌17型免疫而对金黄色葡萄球菌感染的易感性。慢性萎缩性胃炎的病毒加重 与获得细菌感染有关。基于这些原因，我们认为CFTR缺陷的上皮细胞 细胞对17型细胞因子的反应减弱，导致金黄色葡萄球菌感染加重， 流感合并感染加剧了金黄色葡萄球菌的携带。这一假设将在两个具体目标上得到检验。第一, 我们将研究金黄色葡萄球菌在慢性支气管炎患者和对照组人呼吸道上皮细胞上的生长情况。 17型细胞因子对定植的影响。第二，我们将描述17型免疫反应的特征 在鼻腔感染金黄色葡萄球菌的小鼠鼻腔上皮细胞的CF模型中，检查流感是如何影响S. 金色马车。拟议的研究将检查金黄色葡萄球菌感染期间的17型免疫反应 以及流感合并感染如何影响金黄色葡萄球菌在CF的生长。这些研究将有助于阐明寄主病原体。 两种重要呼吸道病原体之间的相互作用和特征 导致慢性阻塞性肺疾病患者肺功能下降。

Abstract Cystic Fibrosis (CF) is a genetic disorder affecting thousands in the United States and worldwide. Loss of function mutations in the CF transmembrane conductance regulator (CFTR), a chloride ion channel, results in abnormal maintenance of airway surface liquid and loss of mucociliary clearance. CF patients suffer from chronic bacterial infection in the lung with limited therapeutic recourse. Staphylococcus aureus is an important Gram-positive organism in the context of CF. With the increasing prevalence of methicillin-resistant S. aureus (MRSA), this bacterium will likely play a greater role in CF pathogenesis in the near future. MRSA colonization is associated with greater declines in lung function in CF and may influenza polymicrobial infections often found in this disease. Our laboratory has previously demonstrated an important role for Type 17 immunity in regulating S. aureus host defense. Type 17 cytokines, IL-17 and IL-22, stimulate antimicrobial peptide production by epithelial cells that are critical to S. aureus clearance. At this time, it is unclear if Type 17 or related antimicrobial responses are aberrant in the context of CF. Further, preceding viral infection increases susceptibility to S. aureus infection by suppressing anti-bacterial Type 17 immunity. Viral exacerbation in CF is associated with acquisition of bacterial infection. For these reasons we propose that CFTR deficient epithelial cells display attenuated responses to Type 17 cytokines resulting in worsened S. aureus infection and that influenza co-infection exacerbates S. aureus carriage. This hypothesis will be tested in two specific aims. First, we will investigate S. aureus biofilm growth on human airway epithelial cells from CF and control patients and the impact of Type 17 cytokines on colonization. Second, we will characterize the Type 17 immune response during nasal S. aureus infection in a murine nasal epithelial model of CF and examine how influenza affects S. aureus carriage. The proposed studies will examine the Type 17 immune response during S. aureus infection and how influenza co-infection affects S. aureus growth in CF. These studies will help clarify host-pathogen interactions in CF and characterize the relationship between two important respiratory pathogens that contribute to a decline in lung function in CF patients.