Synergistic control of acute respiratory pathogens by bacteriophage and the innate immune response

噬菌体和先天免疫反应对急性呼吸道病原体的协同控制

基本信息

批准号：
9797736
负责人：
Laurent DEBARBIEUX
金额：
$ 50.17万
依托单位：
GEORGIA INSTITUTE OF TECHNOLOGY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-08-22 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9797736
关键词：
Acute Acute Pneumonia Acute respiratory infection Address Animals Antibiotics Bacteria Bacterial Infections Bacteriophages Biological Models Cells Clinical Clinical Trials Computer Simulation Critical Illness Cytolysis Data Development Distributional Activity Dose Ecology Effectiveness Effector Cell Environment Exposure to Failure Future Gram-Negative Bacteria Hospitals Hybrids Immune Immune response Immune signaling Immune system Immunocompetent Immunology In Vitro Individual Infection Innate Immune Response Innate Immune System Interdisciplinary Study Joints Lung diseases Lymphoid Lytic Measurement Measures Metabolic Clearance Rate Methods Microbe Modeling Multi-Drug Resistance Mus Non-linear Models Nonlinear Dynamics Outcome Pathogenicity Patients Pneumonia Population Proliferating Pseudomonas aeruginosa Public Health Research Research Personnel Resistance Resolution Respiratory Tract Infections Risk Schedule System Target Populations Techniques Testing Therapeutic Time Translating Treatment Efficacy Treatment Failure United States Viral Virus Work acute infection bacterial resistance base clinical translation commensal bacteria control theory curative treatments data integration density design dosage drug resistant pathogen dynamic system experimental analysis experimental study immunological status immunoregulation improved in vivo innovation insight life history mathematical model mouse model multi-drug resistant pathogen multi-scale modeling multidisciplinary multidrug-resistant Pseudomonas aeruginosa mutant neutrophil novel novel therapeutic intervention optimal control theory pathogen pathogenic bacteria pneumonia model predictive modeling prevent public health relevance respiratory response scale up simulation spatiotemporal synergism trait treatment strategy

项目摘要

Abstract Multi-drug resistant (MDR) bacterial pathogens constitute a critical public health threat. The spread of MDR pathogens in hospitals and in the environment has spurred a multidisciplinary response to develop novel antibiotic alternatives. Bacteriophage (`phage') therapy represents a treatment strategy that can, in principle, specifically eliminate MDR pathogens from animal hosts while minimizing off-target effects on host cells and commensal bacteria. The successful compassionate use of phage therapy for critically ill patients in the United States demonstrates a critical first-step towards large-scale translational deployment of phage therapy. However, prior clinical trials of phage therapeutic efficacy have yielded equivocal results, thereby raising the question: what are the core mechanisms underlying curative treatment of respiratory infections by phage therapy? The use of phage-based therapy presumes that the direct killing action of phage is responsible for pathogen elimination in vivo. In contrast, prior work of the investigators showed that the outcome of in vivo phage therapeutic treatment of acute pneumonia in a murine host depended critically on host immune state. The investigators combined population modeling and experimental analysis to identify a mechanism of `immunophage synergy' to identify criteria when phage therapy works and when it fails. Here, the project will combine population modeling, control theory, data- driven computational simulations, in vitro experiments with phage, bacteria, and neutrophils, and in vivo infection experiments in murine hosts to understand fundamental principles underlying curative treatment of acute respiratory infections. This project will characterize the spatiotemporal drivers of synergistic elimination in vivo as well as develop optimized combinations of phage strains, dosages, and timing to avert therapeutic failure via the proliferation of phage-resistant bacterial mutants across a continuum of immunodeficient hosts. The integrated and multidisciplinary research plans are designed to yield fundamental insights into the mechanism of synergistic elimination of bacterial pathogens by phage and innate effector cells as well as generalizable and rigorous approaches to optimized phage cocktail design when immune responses are compromised.

抽象的多药耐药（MDR）细菌病原体构成了关键的公共卫生威胁。传播医院和环境中的MDR病原体刺激了多学科的反应新型抗生素替代品。噬菌体（“噬菌体”）疗法代表了一种治疗策略，可以原理，专门从动物宿主那里消除了MDR病原体，同时最大程度地减少了对脱靶的影响宿主细胞和共生细菌。成功地使用噬菌体疗法来危重患病美国的患者对大规模翻译部署展示了至关重要的第一步噬菌体疗法。但是，先前的噬菌体治疗疗效临床试验已产生模棱两可结果，从而提出了一个问题：通过噬菌体治疗的呼吸道感染？基于噬菌体的治疗的使用假设是直接杀人噬菌体的作用负责体内消除病原体。相反，调查人员的先前工作表明鼠宿主中急性肺炎的体内噬菌体治疗的结果批判性地取决于宿主免疫状态。调查人员合并了人口建模和实验分析以识别“免疫协同作用”的机制，以确定噬菌体时标准治疗起作用，何时失败。在这里，该项目将结合种群建模，控制理论，数据 - 驱动的计算模拟，噬菌体，细菌和中性粒细胞的体外实验以及体内在鼠宿主中进行的感染实验，以了解治疗治疗基础的基本原理急性呼吸道感染。该项目将表征协同的时空驱动因素消除体内以及开发优化的噬菌体菌株，剂量和时间的组合通过在连续体中持续抗噬菌体的细菌突变体的增殖来避免治疗衰竭免疫缺陷宿主。综合和多学科研究计划旨在产生对通过噬菌体和先天效应细胞以及可推广和严格的方法来优化噬菌体鸡尾酒设计当免疫反应受到损害时。