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.

项目总结：项目3 项目3的总体目标和意义是生成基于鼻腔微生物区系的临床前验证 阻断金黄色葡萄球菌和肺炎链球菌鼻腔定植的治疗方法。我们的 实现这一目标的创新方法是在人的鼻腔器官上培养人的鼻腔细菌。一起， 金黄色葡萄球菌和肺炎链球菌占39%的病例和29%的死亡归因于抗生素耐药性 在美国，鼻腔定植是细菌侵袭性感染的主要来源，并为 它们的传播；阻止殖民既减少了感染，也减少了传播。缺乏有效的疫苗 针对金黄色葡萄球菌或非疫苗血清型肺炎链球菌，迫切需要新的非抗生素。 预防两者感染的方法。目前治疗金黄色葡萄球菌鼻部非殖民化的方法依赖于 外用抗生素，并与抗生素耐药性的上升有时间上的相关性。在这里，我们解决了一个缺口 如何用抗病毒菌群重新填充以改善长期结果的知识。多重 鼻部微生物区系研究报告了当成年人没有金黄色葡萄球菌和当 儿童不会感染肺炎链球菌。例如，良性细菌Dolosigranulum的鼻部定植 软脑膜通常带有无害的棒状杆菌，与儿童肺炎链球菌的缺失有关。在……里面 成年金黄色葡萄球菌鼻腔定植与皮下血吸虫呈负相关。我们的初步数据显示许多 金黄色葡萄球菌菌株在体外对金黄色葡萄球菌的生长有抑制作用。小球藻与棒状杆菌的共培养 在体外，假白喉杆菌对肺炎链球菌的生长有强烈的抑制作用，而不是单独作用。此外， 棒状杆菌能促进小球藻的生长。因此，我们的首要假设是 良性的人类鼻腔细菌可以对金黄色葡萄球菌和肺炎链球菌产生定植抗性，从而防止 这些抗药性威胁的感染和传播。此外，抗病毒肽-粘膜活性裂解剂 噬菌体可能会加强这一点。相互作用的网络支撑着微生物区系的组成。依赖财团可以避免 当添加单个菌株时可能发生意外的社区相互作用的风险，并增加 成功地与期望的社区重新繁殖的可能性。临床试验的一个主要障碍是完全确定 在人类背景下赋予定植抵抗力的良性鼻腔细菌菌株的确定联合体 鼻腔上皮，促进健康、完整的鼻黏膜上皮屏障。我们的有机类化合物培养核心已经成功 产生了人体呼吸道有机物质。因此，我们将利用鼻腔上皮的进展来克服这一障碍 有机化合物与我们在培养人类鼻腔细菌和识别分子机制方面的专业知识相结合 鼻腔微生物区系内的相互作用。用我们常规使用的方法，项目1和有机化合物培养 核心，我们将实现两个目标：识别和表征可复制的人类鼻部微生物联合体1) 保护鼻上皮免受金黄色葡萄球菌/肺炎链球菌的侵袭；2)促进上皮屏障 金黄色葡萄球菌/肺炎链球菌在体外的完整性和阻止上皮侵袭，并确定潜在的机制。