Modeling the synergistic elimination of bacteria by phage and the innate immune system

JOURNAL OF THEORETICAL BIOLOGY

卷:429

Article

Leung, Chung Yin (Joey)^1,2  Weitz, Joshua S.^1,2 

[1] Georgia Inst Technol, Sch Biol Sci, Atlanta, GA 30332 USA

[2] Georgia Inst Technol, Sch Phys, Atlanta, GA 30332 USA

关键词: Bacteriophage;    Phage therapy;    Antibiotic resistance;    Population dynamics;    Mathematical model;   

DOI  :  10.1016/j.jtbi.2017.06.037

来源: Elsevier

【 摘 要 】

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 III 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. (C) 2017 Elsevier Ltd. All rights reserved.

【 授权许可】

Free