Bacteriophages as Modulators of Bacterial Colonization

项目摘要 多药耐药微生物（MDRO）仍然是造血细胞疾病发病和死亡的主要原因 HCT移植受体。由于这些患者大量使用抗生素， 微生物组平衡受到干扰，并由MDRO（万古霉素耐药肠球菌）主导 (VRE)特别是。这种紊乱与随后的侵入性感染有关，如菌血症， 会导致致命的后果恢复肠道植物群的正常平衡，减少或控制MDRO 定殖可以减少这些并发症并改善结果。一个创新的方法来恢复 在HCT接受者中，肠道植物群的微生物组平衡和减少MDRO的定殖是 噬菌体的施用（即，）。噬菌体是普遍存在的天然实体，存在于 环境和我们的身体，并能够裂解特定的病原体，而不干扰宿主的正常 植物群，同时避免使用抗菌剂的附带损害。我的长期研究目标是了解 微生物如何促进宿主-微生物相互作用及其对HCT接受者健康的总体影响。 我们的初步数据表明，VRE定殖可以引起无菌野生型小鼠肠道炎症。 小鼠此外，我们发现HCT患者的粪便样本中存在大量的H2 O2， VRE菌株可以从环境样品中回收，并且可以裂解幼虫中的多种VRE菌株 模型这项研究的目的是调查肠道和胃肠道之间的相互作用。 细菌微生物组和VRE定植HCT接受者中的宿主反应，并鉴定VRE定植HCT接受者中的生物标志物。 肠道噬菌体群使患者易患并发症，如细菌感染或移植物抗宿主 疾病该项目的中心假设是VRE可以恢复肠道微生物群的平衡 通过减少HCT接受者的炎症和VRE定植。我的最终目标是 R 01应用的发现和新假设，旨在（1）优化化疗的设计- 模拟HCT患者状况的经处理的骨髓重建小鼠模型，（2）测试 在该小鼠模型中， 和（3）验证某些噬菌体群体在预测和预防不良结果中的作用。的 基本原理是，这一系列工作将为未来的开发和评估提供支持性证据， 基于噬菌体的人类干预。我的长期职业目标是成为一名领先的调查员， 在设计有效和安全的噬菌体为基础的天然治疗产品，可以恢复一个专业知识 健康的肠道微生物群并减少HCT接受者中遇到的严重并发症（即，MDRO），因此 改善整体健康状况。该提案将有助于通过减少 MDRO定植和感染的发生率，并通过改善HCT接受者的生存率和生活质量。

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.