Bacteriophages as Modulators of Bacterial Colonization

噬菌体作为细菌定植的调节剂

• 批准号: 10350970
• 负责人: Lynn El Haddad
• 金额: $ 10.58万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-12-13 至 2026-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10350970
• 关键词: Address; Anti-Inflammatory Agents; Antibiotics; Applied Research; Bacteremia; Bacteria; Bacterial Infections; Bacteriophages; Bioinformatics; Biological Markers; Biometry; Blood; Blood specimen; Bone Marrow; Buffers; Caudovirales; Centers for Disease Control and Prevention (U.S.); Clinical Data; Communicable Diseases; Data; Development; Environment; Equilibrium; Evaluation; Fatal Outcome; Feces; Future; Germ-Free; Goals; Health; Hematologic Neoplasms; Human; Immune; Immune response; Immune system; Incidence; Individual; Infection; Inflammation; Inflammatory Response; Intervention; Knowledge; Larva; Lead; Microvirus; Mission; Modeling; Monitor; Morbidity - disease rate; Mus; National Institute of Allergy and Infectious Disease; Outcome; Pathology; Patient-Focused Outcomes; Patients; Population; Public Health; Quality of life; RAG1 gene; Rag1 Mouse; Randomized; Research; Research Personnel; Research Project Grants; Research Proposals; Risk; Role; Safety; Sampling; Scheme; Sepsis; Sterility; Testing; Therapeutic; Time; Training; Translating; Transplant Recipients; Transplantation; United States National Institutes of Health; Vancomycin resistant enterococcus; Virus; Wild Type Mouse; Work; World Health Organization; antimicrobial; bacteriome; base; career; chemotherapy; cytokine; design; efficacy testing; experience; experimental study; fight against; gastrointestinal; germ free condition; graft vs host disease; gut colonization; gut microbiome; gut microbiota; hematopoietic cell transplantation; host-microbe interactions; improved; improved outcome; in vivo; in vivo Model; infectious disease model; innovation; insight; microbiome; microbiome analysis; mortality; mouse model; multi-drug resistant pathogen; normal microbiota; pathogen; prevent; reconstitution; restoration; skills; stool sample; synergism

PROJECT SUMMARY Multidrug-resistant organisms (MDROs) remain major causes of morbidity and mortality in hematopoietic cell transplant (HCT) recipients. Because of the substantial use of antibiotics in these patients, their gut microbiome balance is perturbed and becomes dominated by MDROs, vancomycin-resistant enterococci (VRE) in particular. This disturbance is associated with subsequent invasive infections such as bacteremia that can lead to fatal outcome. Restoration of the normal balance of the gut flora and reduction or control of MDRO colonization may curtail these complications and improve outcomes. One innovative approach to restore the microbiome balance of the gut flora and reduce colonization with MDROs in HCT recipients is the administration of bacteriophages (i.e., phages). Phages are ubiquitous and natural entities, present in the environment and in our bodies, and capable of lysing specific pathogens without disturbing the host’s normal flora while averting the collateral damage of antimicrobial usage. My long-term research goal is to understand how phages contribute to host-microbe interactions and their overall impact on the health of HCT recipients. Our preliminary data indicate that VRE colonization can cause inflammation in the gut of germ-free wild-type mice. Additionally, we found that phages are present in high numbers in HCT patients’ stool samples and that VRE phages can be recovered from environmental samples and can lyse a variety of VRE strains in a larva model. The objective of the proposed research is to investigate the interactions between phages, the gut bacterial microbiome, and host responses in VRE-colonized HCT recipients and to identify biomarkers in the gut phage population predisposing patients to complications such as bacterial infections or graft versus host disease. The central hypothesis for this project is that VRE phages can restore balance in the gut microbiota by reducing inflammation and VRE colonization in HCT recipients. My ultimate goal is to generate significant findings and new hypotheses for an R01 application aiming at (1) optimizing the design of a chemotherapy- treated bone marrow-reconstituted mouse model mimicking the condition of HCT patients, (2) testing the efficacy of phages and phages+antibiotic synergy in preventing major MDRO infections in this mouse model, and (3) validating the role of certain phage populations in predicting and preventing poor outcomes. The rationale is that this line of work will provide supportive evidence for future development and evaluation of a phage-based intervention in humans. My long-term career goal is to become a leading investigator with expertise in the design of effective and safe phage-based natural therapeutic products that may restore a healthy gut microbiota and curtail serious complications encountered in HCT recipients (i.e., MDROs), thus improving their overall health outcomes. The proposal will aid in the fight against MDROs by curtailing the incidence of MDRO colonization and infections and by improving survival and quality-of-life of HCT recipients.

项目摘要 抗多药的生物（MDROS）仍然是造血细胞发病和死亡率的主要原因 移植（HCT）接受者。由于这些患者的抗生素大量使用，它们的肠道 微生物组的平衡受到干扰，并由MDROS，抗Vanomycin的肠球菌主导 （vre）特别是。这场灾难与随后的侵入性感染有关，例如细菌 可能导致致命的结果。恢复肠道菌群的正常平衡和减少或控制MDRO 殖民化可能会减少这些并发症并改善结果。一种创新的方法来恢复 肠道菌群的微生物组平衡并减少HCT接受者中MDROS的定殖是 细菌的给药（即噬菌体）。噬菌体是普遍存在的自然实体，存在于 环境和身体中，能够裂解特定的病原体而不会打扰宿主的正常 植物群避免使用抗菌用法的附带损害。我的长期研究目标是了解 噬菌体如何促进宿主微叶互动及其对HCT接受者健康的总体影响。 我们的初步数据表明，VRE定殖可能导致无菌野生型肠道炎症 老鼠。此外，我们发现在HCT患者的粪便样品中，噬菌体数量很高，并且 可以从环境样品中回收VRE噬菌体，并可以在幼虫中裂解各种VRE菌株 模型。拟议研究的目的是研究噬菌体之间的相互作用，肠道 细菌微生物组和VRE殖民化HCT受体中的宿主反应，并鉴定生物标志物 肠道噬菌体种群使患者易于发生，例如细菌感染或移植物与宿主 疾病。该项目的中心假设是VRE噬菌体可以恢复肠道菌群中的平衡 通过减少HCT受体中的炎症和VRE定殖。我的最终目标是产生重要的 针对（1）优化化学疗法设计的R01应用的发现和新假设 处理过的骨髓恢复的小鼠模型模仿了HCT患者的状况，（2）测试 噬菌体和噬菌体的功效+抗生素协同作用在这种小鼠模型中预防主要MDRO感染， （3）验证某些噬菌体种群在预测和预防不良结果中的作用。这 理由是，这项工作将为未来的发展和评估提供支持证据 基于噬菌体的干预人类。我的长期职业目标是成为 设计有效且安全的基于噬菌体的天然治疗产品的专业知识，这些产品可能会恢复 健康的肠道微生物群和降低了HCT接受者（即MDROS）遇到的严重并发症，因此 改善他们的整体健康状况。该提议将通过减少限制 MDRO定殖和感染的发生率，并通过改善HCT接受者的生存和生活质量。