Dynamics of Bacterial-Fungal Interactions in Chronic Lung Infections

慢性肺部感染中细菌-真菌相互作用的动态

• 批准号: 8605291
• 负责人: DEBORAH A HOGAN
• 金额: $ 38.98万
• 依托单位: DARTMOUTH COLLEGE
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-02-10 至 2017-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8605291
• 关键词: Address; Anti-Bacterial Agents; Antibiotic Therapy; Antibiotics; Antibodies; Antifungal Agents; Antifungal Therapy; Aspergillus fumigatus; Asthma; Bacteria; Bacterial Infections; Binding; Biochemical; Candida; Candida albicans; Cell Culture Techniques; Cells; Characteristics; Chronic; Chronic Obstructive Airway Disease; Clinic; Clinical; Clinical Data; Clinical Research; Clinical Trials; Collaborations; Communities; Complex; Cystic Fibrosis; Data; Data Reporting; Development; Disease; Epithelial Cells; Ethanol; Frequencies; Goals; Health; Hereditary Disease; Immunoglobulin G; Individual; Infection; Lead; Lung; Lung diseases; Methods; Microbe; Modeling; Molecular Profiling; Monitor; Mycoses; Outcome; Pathogenesis; Pathway interactions; Patients; Pharmaceutical Preparations; Play; Population; Process; Pseudomonas aeruginosa; Publishing; Pulmonary Cystic Fibrosis; RNA analysis; Relative (related person); Reporting; Research Personnel; Respiratory Failure; Respiratory Tract Infections; Respiratory physiology; Risk Factors; Role; Sampling; Sputum; Technology; Testing; Time; Transcript; Virulence; Work; base; cystic fibrosis patients; experience; fungus; genetic analysis; improved; in vivo; microbial community; microbiome; nano-string; pathogen; pathogenic bacteria; public health relevance; standard of care

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.

描述（由申请人提供）：CF是一种与衰弱和终末肺部感染相关的遗传性疾病。细菌性肺病原体铜绿假单胞菌长期定植于超过80%的CF患者的肺部，并且其存在与患者状况恶化密切相关。然而，很明显，除了铜绿假单胞菌的存在之外，其他因素也会影响铜绿假单胞菌感染患者的肺损伤率和程度。十几项研究发现，真菌也栖息在大多数CF患者的肺部，已发表的临床数据报告了培养物中真菌的存在与肺功能恶化或疾病恶化频率增加之间的相关性。在两项研究中，研究人员发现，同时感染铜绿假单胞菌和真菌（如白色念珠菌或烟曲霉菌）的患者比未感染真菌的患者情况更糟。 基于已发表的和初步的数据，我们假设气道细菌和真菌之间的动力学以两种方式强烈影响CF肺疾病。首先，我们假设在抗菌治疗期间对细菌的抑制导致高真菌负荷，这可能对气道有害（在目标1中测试）。作为这些研究的一部分，我们将与Mitchell Sogin博士（MBL）和Jason Stajich博士（UC滨江）合作，使用从接受全身抗生素治疗的患者中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，细菌群落如何与真菌群落的变化一起变化，以及真菌如何在治疗过程中影响宿主。其次，我们假设铜绿假单胞菌和真菌如C。白色念珠菌和其它念珠菌属（Candida spp.）增加铜绿假单胞菌在混合细菌和真菌感染中的毒力（在目标2中测试）。我们将使用细胞培养模型和临床研究的组合，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）确定真菌定植的CF患者是否会受益于目前仅常规给予CF患者小子集的现有抗真菌治疗，以及（ii）制定用于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内微生物之间发生的相互作用的策略。