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

摘要 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MDR病原体已经刺激了多学科的反应， 新型抗生素替代品。噬菌体（“噬菌体”）疗法代表一种治疗策略， 原则，特别是消除动物宿主的MDR病原体，同时最大限度地减少脱靶效应， 宿主细胞和寄生细菌。噬菌体治疗危重病的成功同情使用 美国的患者展示了迈向大规模平移部署的关键第一步 噬菌体治疗的方法然而，先前的噬菌体治疗效果的临床试验已经产生了模棱两可的结果。 结果，从而提出了一个问题：什么是治愈性治疗的核心机制是什么？ 呼吸道感染用噬菌体治疗使用噬菌体治疗假定直接杀死 噬菌体的作用负责体内病原体的消除。相比之下，调查人员先前的工作 显示在鼠宿主中体内噬菌体治疗急性肺炎的结果 关键取决于宿主的免疫状态研究人员将人口模型和 实验分析，以确定“免疫噬菌体协同作用”的机制， 治疗是否有效在这里，该项目将结合联合收割机人口建模，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 在小鼠宿主中进行感染实验，以了解治愈性治疗的基本原理 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、剂量和时机的优化组合， 通过噬菌体抗性细菌突变体在连续的 免疫缺陷宿主。综合和多学科的研究计划旨在产生 对噬菌体协同消除细菌病原体的机制的基本见解， 以及优化噬菌体混合物设计的可推广和严格的方法 免疫反应受损的时候

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.