Impact of Commensal Corynebacterium Species on Pathogen Colonization and Microbiota Composition

共生棒状杆菌物种对病原体定植和微生物群组成的影响

• 批准号: 10081046
• 负责人: Katherine Paige Lemon
• 金额: $ 30.4万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 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 2021-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10081046
• 关键词: Impact; Commensal; Corynebacterium; Species; Pathogen

 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（由申请人提供）：迫切需要进行功能研究来阐明人类微生物组内不同细菌物种之间的机制相互作用，以了解它们在该微生物群落中的作用。研究表明，非白喉棒状杆菌物种在构建健康的鼻腔和皮肤微生物群方面发挥着重要作用。这些通常无害的共生菌会影响金黄色葡萄球菌和肺炎链球菌的定植，这些病原体也经常定植于鼻/皮肤部位。我们的数据表明，一些棒状杆菌属物种水解人类皮肤表面脂质的类似物，释放具有抗肺炎球菌活性的游离脂肪酸（FFA）。因此，我们假设棒状杆菌属。通过产生脂肪酶来改变它们的栖息地，脂肪酶从宿主上皮表面脂质中释放具有抗菌活性的 FFA，并且这些脂质底物的水平会影响皮肤微生物群的组成，从而减少病原体定植。该提案的总体目标是获得有关共生棒状杆菌属如何产生的遗传和机制知识。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组成。这项研究的基本原理是，揭示这些机制将为鉴定具有治疗用途潜力的特定菌株、基因和/或棒状杆菌产生的化合物创造机会。我们将结合使用基于培养的方法和人类样本来识别相关基因及其表达在培养物和上皮表面的影响。 该提案的具体目标是 (1) 确定棒状杆菌属如何。从宿主脂质中释放抗菌游离脂肪酸，(2) 识别和表征控制脂质需求和脂质非依赖性棒状杆菌属细胞外脂肪酶活性的调节机制。 (3) 确定局部应用的皮肤表面脂质类似物对三种不同人体皮肤部位（干燥、湿润和油性）微生物群的影响。为了实现这些目标，我们将结合使用遗传、生物化学和生物信息学方法（目标 1 和 2），以及基于 16S rRNA 基因的方法（目标 3）。这项工作的意义在于提供鉴定棒状杆菌属特定菌株所急需的基础机制信息。棒状杆菌产生的化合物有可能作为替代的非抗生素疗法来预防肺炎链球菌和金黄色葡萄球菌等病原体的感染。我们策略的三个主要创新是（1）利用共培养细菌的功能分子研究来阐明人类微生物组中不同细菌种类的作用，（2）选择一个允许直接在人类宿主中进行非侵入性研究的系统，以及（3）将我们的研究结果转化为测试对人类皮肤表面的简单干预。我们的长期目标是开发新的可持续方法来管理鼻腔和皮肤微生物群的组成，通过排除或控制病原体来预防疾病。

项目成果

Bacterial microbiota of the nasal passages across the span of human life.

• DOI: 10.1016/j.mib.2017.10.023
• 发表时间: 2018-03
• 期刊: Current opinion in microbiology
• 影响因子: 5.4
• 作者: Bomar L;Brugger SD;Lemon KP
• 通讯作者: Lemon KP

Quantifying Variation in Bacterial Reproductive Fitness: a High-Throughput Method.

量化细菌生殖适应性的变化：一种高通量方法。

• DOI: 10.1128/msystems.01323-20
• 发表时间: 2021-02-02
• 期刊: mSystems
• 影响因子: 6.4
• 作者: Frey PM;Baer J;Bergada-Pijuan J;Lawless C;Bühler PK;Kouyos RD;Lemon KP;Zinkernagel AS;Brugger SD
• 通讯作者: Brugger SD