Nasal Microbial Consortia Combat Antibiotic-Resistant Bacteria

鼻腔微生物联盟对抗抗生素耐药性细菌

• 批准号: 10357970
• 负责人: Katherine Paige Lemon
• 金额: $ 40.04万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-01 至 2026-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10357970
• 关键词: 16S ribosomal RNA sequencing; Address; Adult; Affect; Air; Antibiotic Resistance; Apoptotic; Bacteria; Bacterial Antibiotic Resistance; Bacteriophages; Benign; Biological Assay; Cell Culture Techniques; Cessation of life; Child; Clinical Trials; Coculture Techniques; Collection; Colony-forming units; Combating Antibiotic Resistant Bacteria; Communities; Corynebacterium; Data; Epithelial; Epithelial Attachment; Genome; Growth; Human; Immune response; In Vitro; Infection; Infection prevention; Invaded; Knowledge; Liquid substance; Lytic; Methods; Microscopy; Molecular; Mucous Membrane; Nasal Epithelium; Nose; Organoids; Outcome; Permeability; Persons; Physiology; Population; Production; Reporting; Reproducibility; Resistance; Risk; Sampling; Serotyping; Shapes; Source; Staphylococcus aureus; Streptococcus pneumoniae; Surface; System; Testing; Therapeutic; Tight Junctions; Topical Antibiotic; Vaccines; Validation; Virulence; attenuation; base; colonization resistance; combat; cytokine; experience; fluorescein isothiocyanate dextran; improved; innovation; metabolomics; microbial host; microbiome; microbiota; nasal microbiome; nasal microbiota; nasal swab; pathobiont; pre-clinical; prevent; repaired; response; stem cell derived tissues; transcriptomics; transmission process

PROJECT SUMMARY: Project 3 The overall objective and significance of Project 3 is to generate preclinical validation of nasal microbiota-based therapeutics to block nasal colonization by Staphylococcus aureus and Streptococcus pneumoniae. Our innovative approach to achieve this is to cultivate human nasal bacteria on human nasal organoids. Together, S. aureus and S. pneumoniae account for 39% of cases and 29% of deaths attributed to antibiotic-resistant bacteria in the U.S. Nasal colonization is the primary source of invasive infection by each and the reservoir for their transmission; blocking colonization reduces both infection and transmission. Lacking effective vaccines against S. aureus or nonvaccine serotypes of S. pneumoniae, there is an urgent need for new nonantibiotic approaches to prevent infections by both. Current therapies for nasal decolonization of S. aureus depend on a topical antibiotic and are temporally correlated with rising antibiotic resistance. Here, we address a gap in knowledge in how to repopulate with pathobiont-resistant microbiota to improve long-term outcomes. Multiple nasal microbiota studies report benign bacterial species present when adults are free of S. aureus and when children are free of S. pneumoniae. For example, nasal colonization by the benign bacterium Dolosigranulum pigrum, often with harmless Corynebacterium, is associated with the absence of S. pneumoniae in children. In adults, D. pigrum is inversely associated with S. aureus nasal colonization. Our preliminary data indicate many strains of D. pigrum inhibit S. aureus growth in vitro. Also, cocultivation of D. pigrum with Corynebacterium pseudodiphtheriticum robustly inhibits S. pneumoniae growth in vitro, versus either alone. Moreover, Corynebacterium enhance D. pigrum growth. Thus, our overarching hypothesis is that reproducible consortia of benign human nasal bacteria can confer colonization resistance to S. aureus and S. pneumoniae, preventing infection by and transmission of these antibiotic-resistant threats. Moreover, antipathobiont mucosal-active lytic phage may augment this. Networks of interactions underpin microbiota composition. Relying on consortia avoids the risk of unexpected community interactions that can occur when adding a single strain and increases the likelihood of successful repopulation with a desired community. A major hurdle to clinical trials is to identify fully defined consortia of benign nasal bacterial strains that confer colonization resistance in the context of human nasal epithelium and promote a healthy, intact epithelial barrier. Our Organoid Cultivation Core has successfully generated human airway organoids. Thus, we will overcome this hurdle using advances in nasal epithelial organoids combined with our expertise in cultivating human nasal bacteria and identifying molecular mechanisms of interactions within nasal microbiota. With methods routinely used by us, Project 1 and the Organoid Cultivation Core, we will achieve two aims: identify and characterize reproducible human nasal microbial consortia to 1) protect nasal epithelium from colonization by S. aureus/S. pneumoniae and 2) to promote epithelial barrier integrity and block epithelial invasion by S. aureus/S. pneumoniae in vitro, and identify underlying mechanisms.

项目摘要：项目3 项目3的总体目标和意义是生成基于鼻微生物群的临床前验证 通过金黄色葡萄球菌和肺炎链球菌阻止鼻腔化的疗法。我们的 实现这一目标的创新方法是在人类鼻和类器官上培养人鼻细菌。一起， 金黄色葡萄球菌和肺炎链球菌占病例的39％，死亡的29％归因于抗生素耐药性 美国鼻定植的细菌是每种细菌的主要来源，也是储层的主要来源 他们的传播；阻止定殖可减少感染和传播。缺乏有效的疫苗 反对金黄色葡萄球菌或肺炎链球菌的非疫苗血清型，迫切需要新的非抗生素 预防两者感染的方法。金黄色葡萄球菌鼻非殖民化的当前疗法取决于A 局部抗生素，并在时间上与抗生素耐药性上升相关。在这里，我们解决了一个差距 知识如何用抗病患者的微生物群来改善长期结局。多种的 鼻菌群研究报告说，成年人没有金黄色葡萄球菌和 儿童没有肺炎链球菌。例如，良性细菌鼻植物的鼻定植 pigrum通常患有无害的小杆菌，与儿童缺乏肺炎链球菌有关。在 成年人D. pigrum与金黄色葡萄球菌鼻定植成反比。我们的初步数据表示许多 D. pigrum的菌株在体外抑制金黄色葡萄球菌的生长。此外，d。pigrum与corynebacterium的共培养 假胸腺皮质可稳健地在体外抑制肺炎链球菌的生长，而不是单独抑制肺炎链球菌的生长。而且， Corynebacterium增强了斑纹生长。因此，我们的总体假设是 良性的人鼻细菌可以赋予金黄色葡萄球菌和肺炎链球菌抗性，以防止 这些抗生素抗性威胁的感染和传播。此外，抗磷灰粘粘膜活性裂解 噬菌体可能会增加这一点。相互作用的网络基础菌群组成。依靠财团避免 添加单个压力并增加的社区互动的风险可能发生 成功地与所需的社区重新流产的可能性。临床试验的主要障碍是完全确定 良性鼻细菌菌株的定义联盟，在人类的背景下赋予定殖的抗性 鼻上皮并促进健康，完整的上皮屏障。我们的器官培养核心已成功 产生的人类气道器官。因此，我们将使用鼻中上皮的进步克服这一障碍 类器官结合我们在培养人鼻细菌和鉴定分子机制方面的专业知识 鼻菌群中的相互作用。使用我们通常使用的方法，项目1和类器官培养 核心，我们将实现两个目标：识别和表征可重复的人鼻微生物联盟至1） 保护鼻上皮免受金黄色葡萄球菌/s的定殖。肺炎和2）促进上皮屏障 S. aureus/s的完整性和阻断上皮侵袭。体外肺炎，并鉴定潜在的机制。