Leung Chung Yin Joey, Weitz Joshua S
School of Biological Sciences, Georgia Institute of Technology, Atlanta, Georgia 30332, USA; School of Physics, Georgia Institute of Technology, Atlanta, Georgia 30332, USA.
J Theor Biol. 2017 Sep 21;429:241-252. doi: 10.1016/j.jtbi.2017.06.037. Epub 2017 Jun 28.
Phage therapy has been viewed as a potential treatment for bacterial infections for over a century. Yet, the year 2016 marks one of the first phase I/II human trials of a phage therapeutic - to treat burn wound patients in Europe. The slow progress in realizing clinical therapeutics is matched by a similar dearth in principled understanding of phage therapy. Theoretical models and in vitro experiments find that combining phage and bacteria often leads to coexistence of both phage and bacteria or phage elimination altogether. Both outcomes stand in contrast to the stated goals of phage therapy. A potential resolution to the gap between models, experiments, and therapeutic use of phage is the hypothesis that the combined effect of phage and host immune system can synergistically eliminate bacterial pathogens. Here, we propose a phage therapy model that considers the nonlinear dynamics arising from interactions between bacteria, phage and the host innate immune system. The model builds upon earlier efforts by incorporating a maximum capacity of the immune response and density-dependent immune evasion by bacteria. We analytically identify a synergistic regime in this model in which phage and the innate immune response jointly contribute to the elimination of the target bacteria. Crucially, we find that in this synergistic regime, neither phage alone nor the innate immune system alone can eliminate the bacteria. We confirm these findings using numerical simulations in biologically plausible scenarios. We utilize our numerical simulations to explore the synergistic effect and its significance for guiding the use of phage therapy in clinically relevant applications.
一个多世纪以来，噬菌体疗法一直被视为治疗细菌感染的一种潜在方法。然而，2016年标志着噬菌体治疗首次进入I/II期人体试验阶段之一——在欧洲治疗烧伤患者。在实现临床治疗方面进展缓慢的同时，对噬菌体疗法的理论理解也同样匮乏。理论模型和体外实验发现，噬菌体与细菌结合往往会导致噬菌体和细菌共存，或者噬菌体被完全清除。这两种结果都与噬菌体疗法宣称的目标相悖。噬菌体在模型、实验和治疗应用之间存在差距的一个潜在解决方案是，噬菌体与宿主免疫系统的联合作用可以协同消除细菌病原体这一假说。在此，我们提出一种噬菌体疗法模型，该模型考虑了细菌、噬菌体和宿主先天免疫系统之间相互作用产生的非线性动力学。该模型在早期研究的基础上，纳入了免疫反应的最大能力以及细菌的密度依赖性免疫逃逸。我们通过分析确定了该模型中的一个协同机制，在这个机制中，噬菌体和先天免疫反应共同作用以消除目标细菌。至关重要的是，我们发现在这个协同机制中，单独的噬菌体或单独的先天免疫系统都无法消除细菌。我们在生物学上合理的场景中使用数值模拟来证实这些发现。我们利用数值模拟来探索协同效应及其在指导噬菌体疗法在临床相关应用中的意义。
