Berryhill Brandon A, Gil-Gil Teresa, Levin Bruce R
Department of Biology, Emory University, Atlanta, Georgia, 30322, USA.
bioRxiv. 2025 Apr 10:2025.04.10.648192. doi: 10.1101/2025.04.10.648192.
Studies of antimicrobial therapeutics have traditionally neglected the contribution of the host in determining the course of treatment and its outcome. One critical host element, which shapes the dynamics of treatment is the innate immune system. Studies of chemotherapeutics and complementary therapies such as bacteriophage (phage), are commonly performed with mice that purposely have an ablated innate immune system. Here, we generate a mathematical and computer-simulation model of the joint action of antibiotics, phage, and phagocytes. Our analysis of this model highlights the need for future studies to consider the role of the host's innate immune system in determining treatment outcomes. Critically, our model predicts that the conditions under which resistance to the treatment agent(s) will emerge are much narrower than commonly anticipate. We also generate a second model to predict the dynamics of treatment when multiple phages are used. This model provides support for the application of cocktails to treat infections rather than individual phages. Overall, this study provides hypotheses that can readily be tested experimentally with both and experiments.
对抗菌疗法的研究传统上忽视了宿主在决定治疗过程及其结果方面的作用。塑造治疗动态的一个关键宿主因素是先天免疫系统。化疗和诸如噬菌体等补充疗法的研究通常是在特意去除先天免疫系统的小鼠身上进行的。在这里,我们生成了一个抗生素、噬菌体和吞噬细胞联合作用的数学和计算机模拟模型。我们对该模型的分析强调了未来研究需要考虑宿主先天免疫系统在决定治疗结果中的作用。至关重要的是,我们的模型预测,对治疗药物产生耐药性的条件比通常预期的要窄得多。我们还生成了第二个模型来预测使用多种噬菌体时的治疗动态。该模型为应用鸡尾酒疗法治疗感染而不是单个噬菌体提供了支持。总体而言,本研究提供了可以通过实验和实验轻松检验的假设。