Synergistic elimination of bacteria by phage and the innate immune system

Abstract

Phage therapy has been viewed as a potential treatment for bacterial infections for over a century. Yet, the year 2016 marks the first phase I/II human trial 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.

Rekindling of a Masterful Precedent; Bacteriophage: Reappraisal and Future Pursuits

“…A proof-of-principle is Artilysin, a product recently put on the market. It is unprecedentedly comprised of certain endolysins together with added peptides active against lipopolysaccharides (the impervious component of gram negative bacteria cell membrane) ( Delbrück, 1940 ; Singla et al., 2015 ; Chadha et al., 2017 ; Leung and Weitz, 2017 ). This unique combination merged two different features: bactericidal effect of endolysin plus permeation enhancement activity of the peptides.…”

“…The Second arm to phage kinetics is actually disregarded most of the time. It is simply interested in the key parameters governing the virion-bacterium interaction and so, the phage titer throughout the infection time ( Leung and Weitz, 2017 ). They are specific for each duplet and might show difference according to circumstances; whether in-vivo or in-vitro.…”