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对基于鼻腔微生物群的临床前验证进行验证。 阻止金黄色葡萄球菌和肺炎链球菌鼻定植的治疗方法。我们的 实现这一目标的创新方法是在人鼻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抗生素耐药性所致病例的 39% 和死亡人数的 29% 在美国，鼻腔定植细菌是侵入性感染的主要来源，也是细菌的储存库。 它们的传输；阻断定植可减少感染和传播。缺乏有效的疫苗 针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。目前金黄色葡萄球菌鼻去定植的治疗方法取决于 局部抗生素，并且与抗生素耐药性的上升在时间上相关。在这里，我们解决了一个差距 有关如何重新填充具有抗病微生物群以改善长期结果的知识。多种的 鼻腔微生物群研究报告称，当成年人不含金黄色葡萄球菌时，以及当 儿童没有肺炎链球菌。例如，良性细菌 Dolosigrinum 的鼻定植 猪，通常带有无害的棒状杆菌，与儿童肺炎链球菌的缺乏有关。在 成人中，D. Pigrum 与金黄色葡萄球菌鼻定植呈负相关。我们的初步数据表明许多 D. Pigrum 菌株在体外抑制金黄色葡萄球菌生长。此外，D. Pigrum 与棒状杆菌的共培养 与单独使用任一种药物相比，假白喉杆菌在体外可有效抑制肺炎链球菌的生长。而且， 棒状杆菌促进 D. Pigrum 生长。因此，我们的首要假设是可重复的联盟 良性人类鼻腔细菌可以赋予金黄色葡萄球菌和肺炎链球菌定植抗性，从而预防 这些抗生素耐药性威胁的感染和传播。此外，抗病原体粘膜活性溶解 噬菌体可能会增强这一点。相互作用网络支撑着微生物群的组成。依靠财团避免 添加单一菌株并增加 成功重新填充所需社区的可能性。临床试验的一个主要障碍是充分识别 确定的良性鼻细菌菌株联盟，在人类环境中赋予定植抗性 鼻上皮并促进健康、完整的上皮屏障。我们的类器官培养核心已成功 生成人类气道类器官。因此，我们将利用鼻上皮的进展克服这一障碍 类器官与我们在培养人类鼻细菌和识别分子机制方面的专业知识相结合 鼻腔微生物群内的相互作用。采用我们常用的方法，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类鼻腔微生物群落，以：1) 保护鼻上皮免受金黄色葡萄球菌/S. 的定植。肺炎杆菌和 2) 促进上皮屏障 完整性并阻止金黄色葡萄球菌/S.的上皮侵袭。肺炎体外，并确定潜在机制。