Bacteriophages as Modulators of Bacterial Colonization

项目总结 多药耐药生物(MDRO)仍然是造血细胞发病和死亡的主要原因 移植(HCT)接受者。由于这些患者大量使用抗生素，他们的肠道 微生物群平衡被扰乱，并由耐多药耐药肠球菌和万古霉素耐药肠球菌主导 尤其是(Vre)。这种紊乱与随后的侵袭性感染有关，例如菌血症 会导致致命的后果。恢复肠道菌群的正常平衡和减少或控制MDRO 殖民可能会减少这些并发症并改善结果。一个创新的方法来恢复 HCT受者肠道菌群平衡和减少MDRO定植是 给药噬菌体(即噬菌体)。噬菌体是无处不在的自然实体，存在于 在环境和我们的身体内，并能够在不干扰宿主正常的情况下裂解特定的病原体 菌群，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 噬菌体如何促进宿主-微生物的相互作用及其对血细胞移植受者健康的整体影响。 我们的初步数据表明，VRE的定植可以导致无菌野生型的肠道炎症 老鼠。此外，我们发现在HCT患者的粪便样本中存在大量的噬菌体，并且 VRE噬菌体可以从环境样本中回收，并可以裂解幼虫中的各种VRE毒株 模特。这项拟议的研究的目的是研究噬菌体、肠道之间的相互作用 VRE定植的HCT受者的细菌微生物群和宿主反应，并确定 肠道噬菌体使患者容易发生细菌感染或移植物抗宿主等并发症 疾病。该项目的中心假设是VRE噬菌体可以恢复肠道微生物区系的平衡 通过减少HCT受者的炎症和VRE定植。我的最终目标是产生显著的 R01应用的发现和新的假设旨在(1)优化化疗的设计- 经处理的骨髓重组小鼠模型，模拟HCT患者的情况，(2)测试 噬菌体和噬菌体抗生素协同作用预防小鼠模型中主要MDRO感染的有效性， 以及(3)验证某些噬菌体种群在预测和预防不良结果中的作用。这个 理由是，这项工作将为未来开发和评估 以噬菌体为基础的人类干预。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基于噬菌体的天然治疗产品方面的专业知识，可能会恢复 健康的肠道微生物区系，减少HCT受者(即MDRO)遇到的严重并发症，因此 改善他们的整体健康状况。该提案将通过减少 减少耐多药耐药菌定植和感染的发生率，并改善血细胞移植受者的存活率和生活质量。

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.