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健康威胁。病毒的传播 医院和环境中的多药耐药病原体已经刺激了多学科的反应 新型抗生素替代品。噬菌体疗法代表了一种治疗策略，可以在 原则，特别是从动物宿主中消除MDR病原体，同时将偏离目标的影响降至最低 宿主细胞和共生菌。成功地同情地使用噬菌体疗法治疗危重病人 美国患者向大规模翻译部署迈出了关键的第一步 噬菌体疗法。然而，先前关于噬菌体治疗效果的临床试验结果并不明确。 结果，从而提出了一个问题：什么是根治的核心机制 噬菌体疗法引起的呼吸道感染？基于噬菌体的疗法的使用假设直接杀死 在体内，噬菌体的作用负责消除病原体。相比之下，调查人员之前的工作 表明体内噬菌体疗法治疗小鼠急性肺炎的结果 严重依赖于宿主的免疫状态。研究人员结合了人口建模和 噬菌体免疫协同识别标准的实验分析 治疗奏效了，当它失败了。在这里，该项目将结合人口建模、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 体内消除以及发展噬菌体菌株、剂量和时机的优化组合 通过抗噬菌体突变株在连续的 免疫缺陷宿主。综合和多学科的研究计划旨在产生 噬菌体与细菌协同清除病原体机理的基本认识 天然效应细胞以及可推广和严格的优化噬菌体鸡尾酒设计方法 当免疫反应受损时。

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.