Bacteriophages as Modulators of Bacterial Colonization

噬菌体作为细菌定植的调节剂

基本信息

批准号：
10540393
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
项目类别：
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/10540393
关键词：
Address Anti-Inflammatory Agents Antibiotics Applied Research Bacteremia Bacteria Bacterial Infections Bacteriophages Bioinformatics 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 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 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 biomarker identification career chemotherapy cytokine design efficacy testing experience experimental study fighting 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 risk mitigation skill acquisition stool sample synergism

项目摘要

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.

项目概要多重耐药微生物（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，他们的肠道受到影响。微生物组平衡受到扰乱，并由多重耐药菌（MDRO）、万古霉素耐药肠球菌主导（VRE）尤其与随后的侵袭性感染有关，例如菌血症。肠道菌群正常平衡的恢复以及 MDRO 的减少或控制可能导致致命的结果。定殖可以减少这些并发症并改善结果。 HCT 受者肠道菌群的微生物组平衡和减少 MDRO 的定植是噬菌体（即噬菌体）的施用是普遍存在的天然实体，存在于体内。环境和我们体内的细菌，能够在不干扰宿主正常功能的情况下裂解特定的病原体我的长期研究目标是了解菌群，同时避免使用抗菌药物造成的附带损害。噬菌体如何促进宿主-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 定植可引起无菌野生型肠道炎症此外，我们发现 HCT 患者的粪便样本中存在大量噬菌体。 VRE 噬菌体可以从环境样本中回收，并且可以裂解幼虫中的多种 VRE 菌株该模型的目的是研究噬菌体和肠道之间的相互作用。细菌微生物组、VRE 定植的 HCT 接受者的宿主反应以及对生物标记物的识别肠道噬菌体群体使患者容易出现细菌感染或移植物抗宿主等并发症该项目的中心假设是 VRE 噬菌体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，我的最终目标是产生显着的效果。 R01 应用的发现和新假设旨在 (1) 优化化疗的设计- 模拟 HCT 患者状况的经过治疗的骨髓重建小鼠模型，（2）测试噬菌体和噬菌体+抗生素协同作用在预防该小鼠模型中主要MDRO感染方面的功效， (3) 验证某些噬菌体群体在预测和预防不良结果中的作用。理由是，这一工作将为未来的开发和评估提供支持性证据我的长期职业目标是成为基于噬菌体的人类干预的领先研究者。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，这些产品可以恢复健康的肠道微生物群并减少 HCT 受者（即 MDRO）遇到的严重并发症，从而该提案将通过减少多重耐药菌来帮助对抗多重耐药菌。减少 MDRO 定植和感染的发生率，并提高 HCT 接受者的生存率和生活质量。