Impact of commensal Corynebacterium species on pathogen colonization and microbiota composition

共生棒杆菌属对病原体定植和微生物群组成的影响

• 批准号: 9006947
• 负责人: Katherine Paige Lemon
• 金额: $ 37.7万
• 依托单位: ADA FORSYTH INSTITUTE, INC.
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-02-01 至 2020-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9006947
• 关键词: 7 year old; Accounting; Affect; Anterior nares; Anti-Bacterial Agents; Bacteria; Biochemical; Bioinformatics; Biological Assay; Biota; Cessation of life; Child; Coculture Techniques; Corynebacterium; Data; Development; Disease; Ear; Elbow; Environment; Epithelial; Esters; Fatty Acids; Forearm; Genes; Genetic; Genus staphylococcus; Goals; Growth; Habitats; Health Benefit; Human; Human Microbiome; In Vitro; Infection; Infection prevention; Intervention; Knowledge; Lead; Lipase; Lipids; Mediating; Methicillin Resistance; Modeling; Modification; Molecular; Morbidity - disease rate; Nasal cavity; Nonesterified Fatty Acids; Nose; Oleic Acids; Olive oil preparation; Play; Population; Probiotics; Production; Public Health; Research; Risk; Role; Sampling; Site; Skin; Staphylococcus aureus; Streptococcus; Streptococcus pneumoniae; Structure; Surface; System; Testing; Therapeutic Uses; Topical application; Translating; Triglycerides; Triolein; Vision; Work; analog; antimicrobial; base; extracellular; in vivo; innovation; member; microbial community; microbiota; mortality; novel; novel strategies; pathogen; preference; prevent; public health relevance; rRNA Genes; resistant strain

 DESCRIPTION (provided by applicant): Functional studies to elucidate mechanistic interactions between different bacterial species within the human microbiome are critically needed to understand their role in this microbial community. Research suggests that non-diphtheriae Corynebacterium species play a significant role in structuring healthy nasal and skin microbiota. These generally harmless commensals are implicated in affecting colonization by Staphylococcus aureus and Streptococcus pneumoniae, pathogens that also frequently colonize nasal/skin sites. Our data indicate that some Corynebacterium species hydrolyze analogs of human skin-surface lipids releasing free fatty acids (FFAs) with anti-pneumococcal activity. Thus, we hypothesize that Corynebacterium spp. modify their habitat by producing lipases that release FFAs with antibacterial activity from host epithelial-surface lipids and that the level of these lipid substrates impacts the composition of the skin microbiota, diminishing pathogen colonization. The overall objective of this proposal is to gain genetic and mechanistic knowledge of how commensal Corynebacterium spp. release these antibacterial FFAs from host surface lipids and to determine if altering skin lipid composition affects microbiota composition. The rationale for this study is that uncovering these mechanisms will create opportunities to identify specific strains, genes and/or Corynebacterium-produced compounds with potential for therapeutic use. We will use a combination of culture-based approaches and human samples to identify relevant genes, and the impact of their expression, in culture and on epithelial surfaces. The Specific Aims of this proposal are (1) to determine how Corynebacterium spp. release antibacterial free fatty acids from host lipids, (2) to identify and characterize the regulatory mechanisms that control activity of extracellular lipases in lipid-requiring and lipid-independent Corynebacterium spp. and (3) to determine the impact of a topically applied skin-surface-lipid analog on the microbiota of three different human skin sites (dry, moist and oily). To accomplish these, we will use a combination of genetic, biochemical and bioinformatic approaches (Aims 1 and 2), along with a 16S rRNA gene-based approach (Aim 3). The significance of this work will be to provide the foundational mechanistic information that is critically needed to identify specifc strains of Corynebacterium spp. and Corynebacterium-produced compounds with potential as alternative, non-antibiotic therapies to prevent infections by pathogens, such as S. pneumoniae and S. aureus. The three main innovations in our strategy are (1) using functional molecular studies of bacteria in coculture to elucidate the role of different bacterial species within the human microbiome, (2) choosing a system that allows for non-invasive studies directly in the human host, and (3) translating our findings to test a simple intervention on human skin surfaces. Our long-term goal is to develop new and sustainable ways to manage the composition of nasal and skin microbiota to prevent disease by excluding or controlling pathogens.

 描述（由适用提供）：至关重要的是阐明人类微生物组中不同细菌物种之间机械相互作用的功能研究，以了解其在这个微生物群落中的作用。研究表明，非白喉菌群物种在结构健康的鼻和皮肤菌群中起着重要作用。这些通常无害的共生含义在影响金黄色葡萄球菌和肺炎链球菌的定殖时暗示，这些病原体也经常在鼻/皮肤部位定植。我们的数据表明，一些corynebacterium种类水解了人类皮肤表面脂质的类似物，它们释放了具有抗巨炎活性的游离脂肪酸（FFA）。那我们假设Corynebacterium spp。通过产生脂肪酶从宿主上皮表面脂质释放FFA的脂肪酶来修饰其栖息地，并且这些脂质底物的水平会影响皮肤菌群的组成，从而减少病原体定殖。该提案的总体目的是获取有关共同核酸杆菌属的遗传和机械知识。从宿主表面脂质中释放这些抗菌FFA，并确定改变皮肤脂质成分是否会影响微生物群的组成。这项研究的理由是，发现这些机制将创造机会，以识别具有治疗用途潜力的特定菌株，基因和/或corynebacterum生产的化合物。我们将使用基于培养的方法和人类样本的组合来鉴定相关基因及其表达，在培养和上皮表面上的影响。 该提案的具体目的是（1）确定Corynebacterium spp的方式。 （2）释放从宿主脂质中释放抗菌游离脂肪酸，以识别和表征控制细胞外脂肪酶在脂质重质和脂质独立的corynebacterium spp中的活性的调节机制。 （3）确定额外施加的皮肤表面脂质类似物对三种不同人类皮肤部位（干燥，湿润和油性）的微生物群的影响。为了实现这些作用，我们将结合遗传，生化和生化方法（目标1和2）以及基于16S rRNA基因的方法（AIM 3）。这项工作的意义将是提供基础机械信息，这些信息非常需要识别corynebacterium spp的特定菌株。和甲虫生产的化合物，具有潜力，可作为替代性的非抗生素疗法，以防止病原体（例如肺炎链球菌和金黄色葡萄球菌）感染。我们策略中的三个主要创新是（1）使用结合中细菌的功能性分子研究来阐明人类微生物组中不同细菌物种的作用，（2）选择一个直接在人类宿主中进行非侵入性研究的系统，以及（3）对人类皮肤表面进行简单的干预，以测试我们的发现，以测试一项简单的干预。我们的长期目标是开发新的和可持续的方法来管理鼻和皮肤菌群的组成，以通过排除或控制病原体来预防疾病。