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：
10461723
负责人：
Laurent DEBARBIEUX
金额：
$ 48.81万
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/10461723
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 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 Disease 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 rational design respiratory respiratory pathogen 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.

抽象的多重耐药（MDR）细菌病原体构成了严重的公共卫生威胁。的传播医院和环境中的耐多药病原体激发了多学科的反应，以开发新型抗生素替代品。噬菌体（“噬菌体”）疗法代表了一种治疗策略，可以原则上，专门消除动物宿主中的 MDR 病原体，同时最大限度地减少对动物宿主的脱靶影响宿主细胞和共生细菌。噬菌体疗法成功用于危重病人的富有同情心的治疗美国患者向大规模转化部署迈出了关键的第一步噬菌体疗法。然而，先前噬菌体治疗功效的临床试验得出了模棱两可的结果结果，从而提出了一个问题：治愈性治疗的核心机制是什么？噬菌体疗法治疗呼吸道感染？使用基于噬菌体的疗法假定直接杀死噬菌体的作用负责体内病原体的消除。相比之下，研究人员之前的工作显示体内噬菌体治疗小鼠宿主急性肺炎的结果很大程度上取决于宿主的免疫状态。研究人员结合人口模型和实验分析以确定“免疫噬菌体协同作用”的机制，以确定噬菌体时的标准治疗有效以及失败时。在这里，该项目将结合人口建模、控制理论、数据- 驱动计算模拟、噬菌体、细菌和中性粒细胞的体外实验以及体内实验在小鼠宿主中进行感染实验，以了解治疗的基本原理急性呼吸道感染。该项目将描述协同的时空驱动因素体内消除以及开发噬菌体菌株、剂量和时间的优化组合通过噬菌体抗性细菌突变体在连续体中的增殖来避免治疗失败免疫缺陷的宿主。综合和多学科研究计划旨在产生对噬菌体和细菌病原体协同消除机制的基本见解先天效应细胞以及优化噬菌体鸡尾酒设计的通用且严格的方法当免疫反应受到损害时。