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: 9197309
• 负责人: DEBORAH A HOGAN
• 金额: $ 35.85万
• 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 2018-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9197309
• 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; Pathogenesis; Pathway interactions; Patient-Focused Outcomes; Patients; Pharmaceutical Preparations; Play; Population; Process; Pseudomonas aeruginosa; Publishing; Pulmonary Cystic Fibrosis; Pulmonary Fibrosis; RNA analysis; Reporting; Research Personnel; Respiratory Failure; Respiratory Tract Infections; Respiratory physiology; Risk Factors; Role; Sampling; Sputum; Technology; Testing; Time; Transcript; Virulence; Work; base; co-infection; 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期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慢性定植在超过80%的CF患者的肺部，其存在与患者病情恶化密切相关。然而，很明显，铜绿假单胞菌存在之外的其他因素影响铜绿假单胞菌感染患者肺损伤的发生率和程度。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，铜绿假单胞菌和真菌（如白色念珠菌或烟曲霉）共同定植的患者比没有真菌共同定植的患者情况更糟。根据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在两个方面强烈影响CF肺部疾病。首先，我们假设在抗菌治疗期间抑制细菌导致高真菌负荷，这可能对气道有害（在Aim 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（UC Riverside）合作，利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。其次，我们假设铜绿假单胞菌与真菌（如白色念珠菌和其他念珠菌）之间的分子相互作用增加了铜绿假单胞菌在混合细菌和真菌感染中的毒力（在Aim 2中进行了测试）。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：(1)确定真菌定殖的CF患者是否会从现有的抗真菌治疗中受益，这些治疗目前只对一小部分CF患者进行常规治疗；(2)制定分析其他慢性、涉及真菌和细菌的多微生物感染的策略，以及多微生物群落中微生物之间发生的相互作用。

项目成果

Profiling of Bacterial and Fungal Microbial Communities in Cystic Fibrosis Sputum Using RNA.

使用 RNA 对囊性纤维化痰中的细菌和真菌微生物群落进行分析。

• DOI: 10.1128/msphere.00292-18
• 发表时间: 2018
• 期刊: mSphere
• 影响因子: 4.8
• 作者: Grahl,Nora;Dolben,EmilyL;Filkins,LauraM;Crocker,AlexW;Willger,SvenD;Morrison,HilaryG;Sogin,MitchellL;Ashare,Alix;Gifford,AlexH;Jacobs,NicholasJ;Schwartzman,JosephD;Hogan,DeborahA
• 通讯作者: Hogan,DeborahA

Candida albicans interactions with bacteria in the context of human health and disease.

• DOI: 10.1371/journal.ppat.1000886
• 发表时间: 2010-04-29
• 期刊: PLoS pathogens
• 影响因子: 6.7
• 作者: Morales DK;Hogan DA
• 通讯作者: Hogan DA