Dynamics of Bacterial-Fungal Interactions in Chronic Lung Infections

描述(申请人提供)：慢性萎缩性肺病是一种遗传性疾病，与衰弱和终末期肺部感染有关。肺部细菌铜绿假单胞菌长期定植在超过80%的CF患者的肺部，它的存在与患者病情的恶化密切相关。然而，除了铜绿假单胞菌的存在外，很明显，其他因素会影响铜绿假单胞菌感染患者的肺损伤的速度和程度。十多项研究发现，真菌也存在于大多数CF患者的肺部，发表的临床数据报告称，培养中真菌的存在与肺功能恶化或疾病恶化的频率之间存在相关性。在两项研究中，研究人员发现，同时患有铜绿假单胞菌和真菌(如白色念珠菌或烟曲霉)的患者，比那些没有同时受到真菌侵袭的患者的情况更差。基于已发表的和初步的数据，我们假设呼吸道细菌和真菌之间的动态在两个方面强烈地影响着慢性肺疾病。首先，我们假设在抗菌治疗期间对细菌的抑制会导致高真菌负荷，这可能对呼吸道有害(在目标1中进行了测试)。作为这些研究的一部分，我们将与Mitchell Sogin博士(MBL)和Jason Stajich博士(加州大学河滨分校)合作，使用从接受全身抗生素治疗的患者纵向收集的临床样本，开发真菌群落分析方法。除了分析真菌种类的变化外，我们还将确定特定真菌的绝对水平是否增加，细菌群落如何随着真菌群落的变化而变化，以及真菌在治疗过程中如何影响宿主。第二，我们假设铜绿假单胞菌与白色念珠菌和其他念珠菌等真菌之间的分子相互作用。在细菌和真菌混合感染中增加铜绿假单胞菌的毒力(在目标2中测试)。我们将结合细胞培养模型和临床研究，结合尖端的RNA分析方法，在迭代过程中了解CF肺中细菌和真菌的动态。我们的长期目标是：(I)确定被真菌定植的CF患者是否会从现有的抗真菌疗法中受益，这些疗法目前只对一小部分CF患者进行常规治疗，以及(Ii)开发分析涉及真菌和细菌的其他慢性、多微生物感染以及多微生物群落中微生物之间的相互作用的策略。

DESCRIPTION (provided by applicant): CF is a genetic disease associated with debilitating and terminal lung infections. The bacterial lung pathogen Pseudomonas aeruginosa chronically colonizes the lungs of more than 80% of patients with CF, and its presence is strongly associated with worse patient status. However, it is clear that factors other than the presence of P. aeruginosa impact the rate and extent of lung damage in P. aeruginosa-infected patients. More than a dozen studies have found that fungi also inhabit the lungs of the majority of individuals with CF, published clinical data report correlations between the presence of fungi in culture and worse lung function or increased frequency of disease exacerbations. In two studies, researchers found that patients colonized with both P. aeruginosa and fungi, such as Candida albicans or Aspergillus fumigatus, were worse off than those not co-colonized by fungi. Based on published and preliminary data, we hypothesize that the dynamics between airway bacteria and fungi strongly impact CF lung disease in two ways. First, we hypothesize that the suppression of bacteria during periods of antibacterial therapy leads to high fungal loads that can be harmful to airways (tested in Aim 1). As part of these studies, we will develop methods for the analysis of fungal communities in collaboration with Dr. Mitchell Sogin (MBL) and Dr. Jason Stajich, (UC Riverside) using longitudinally collected clinical samples from patients undergoing systemic antibiotic therapy. In addition to analysis of the changes in fungi species, we will determine if specific fungi increase in absolute levels, how the bacterial communities change in conjunction with changes in the fungal communities, and how fungi impact the host over the course of treatment. Second, we hypothesize that molecular interactions between P. aeruginosa and fungi such as C. albicans and other Candida spp. increase P. aeruginosa virulence in mixed bacterial and fungal infections (tested in Aim 2). We will use a combination of cell culture models and clinical studies, in combination with cutting edge RNA analysis methods, in an iterative process to understand the dynamics of bacteria and fungi in the CF lung. Our long term goals are: (i) to determine if CF patients colonized with fungi would benefit from existing antifungal therapies that are currently only routinely administered to a small subset of CF patients, and (ii) to develop strategies for the analysis of other chronic, polymicrobial infections involving fungi and bacteria, and the interactions that occur between microbes within polymicrobial communities.