噬菌体治疗急性铜绿假单胞菌肺部感染的群体模型。

IF 5 2区 生物学 Q1 MICROBIOLOGY mSystems Pub Date : 2024-10-22 Epub Date: 2024-09-04 DOI:10.1128/msystems.00171-24
Rogelio A Rodriguez-Gonzalez, Quentin Balacheff, Laurent Debarbieux, Jacopo Marchi, Joshua S Weitz
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引用次数: 0

摘要

耐多药(MDR)病原菌引起的感染是一个全球性的健康威胁。噬菌体("噬菌体")越来越多地被用作治疗多重耐药细菌感染患者的替代疗法或最后手段。然而,噬菌体疗法的治疗效果可能会受到治疗过程中出现的噬菌体抗药性和/或阻碍体内噬菌体与细菌相互作用的物理限制。在这项研究中,我们评估了肺部空间结构对噬菌体疗法治疗铜绿假单胞菌感染疗效的影响。为此,我们根据支气管树的几何形状开发了一个空间结构元种群网络模型,包括宿主先天性免疫反应和噬菌体抗性细菌突变体的出现。我们模拟了细菌、噬菌体和宿主先天免疫系统在气道(节点)层面上的生态相互作用。该模型预测,在先天性免疫活性充足和噬菌体诱导的高效裂解作用下,噬菌体和中性粒细胞的联合作用将协同消除铜绿假单胞菌感染。元群体模型模拟还预测,MDR 细菌在支气管树远端结节的清除速度更快。值得注意的是,对野生型小鼠和淋巴细胞耗竭型小鼠肺组织时间序列的图像分析显示了一种一致的、具有统计学意义的模式:肺底部的感染强度先于肺顶部的感染强度被清除。总之,结合使用模拟和体内实验图像分析,进一步支持了使用噬菌体疗法治疗铜绿假单胞菌引起的急性肺部感染,同时强调了在先天免疫反应受损和/或噬菌体诱导的裂解效率低下的空间结构环境中治疗的潜在局限性:噬菌体疗法越来越多地被用作治疗耐多药(MDR)细菌引起的严重感染的同情疗法。然而,在大型临床研究中观察到的结果喜忧参半,这凸显出在了解噬菌体疗法的成败方面存在差距。我们团队之前的研究利用体内实验和单室数学模型证明,尽管出现了噬菌体耐药菌,但噬菌体和中性粒细胞能协同清除急性铜绿假单胞菌肺炎。事实上,肺部环境是高度结构化的,这就提出了一个问题:在结合现实物理连接性的情况下,免疫噬菌体的协同作用能否解释铜绿假单胞菌肺炎的治疗效果?为了解决这个问题,我们开发了一个模仿肺部分支结构的元群体网络模型,以评估噬菌体疗法对 MDR 铜绿假单胞菌肺炎的疗效。该模型预测了噬菌体和中性粒细胞对铜绿假单胞菌的协同清除作用,但强调了空间结构环境中的潜在挑战,表明要成功清除细菌可能需要更高的先天免疫水平。模型模拟揭示了病原体清除的空间模式,即支气管树远端结节的铜绿假单胞菌清除速度快于初级结节。有趣的是,对受感染小鼠的图像分析表明了一种一致且具有统计学意义的模式:感染强度在肺底部先于顶部清除。建模和图像分析的结合使用支持了噬菌体疗法在急性铜绿假单胞菌肺炎中的应用,同时也强调了在空间结构的体内环境中治疗成功所面临的潜在挑战,包括先天性免疫反应受损和噬菌体疗效降低。
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Metapopulation model of phage therapy of an acute Pseudomonas aeruginosa lung infection.

Infections caused by multidrug resistant (MDR) pathogenic bacteria are a global health threat. Bacteriophages ("phage") are increasingly used as alternative or last-resort therapeutics to treat patients infected by MDR bacteria. However, the therapeutic outcomes of phage therapy may be limited by the emergence of phage resistance during treatment and/or by physical constraints that impede phage-bacteria interactions in vivo. In this work, we evaluate the role of lung spatial structure on the efficacy of phage therapy for Pseudomonas aeruginosa infections. To do so, we developed a spatially structured metapopulation network model based on the geometry of the bronchial tree, including host innate immune responses and the emergence of phage-resistant bacterial mutants. We model the ecological interactions between bacteria, phage, and the host innate immune system at the airway (node) level. The model predicts the synergistic elimination of a P. aeruginosa infection due to the combined effects of phage and neutrophils, given the sufficient innate immune activity and efficient phage-induced lysis. The metapopulation model simulations also predict that MDR bacteria are cleared faster at distal nodes of the bronchial tree. Notably, image analysis of lung tissue time series from wild-type and lymphocyte-depleted mice revealed a concordant, statistically significant pattern: infection intensity cleared in the bottom before the top of the lungs. Overall, the combined use of simulations and image analysis of in vivo experiments further supports the use of phage therapy for treating acute lung infections caused by P. aeruginosa, while highlighting potential limits to therapy in a spatially structured environment given impaired innate immune responses and/or inefficient phage-induced lysis.

Importance: Phage therapy is increasingly employed as a compassionate treatment for severe infections caused by multidrug-resistant (MDR) bacteria. However, the mixed outcomes observed in larger clinical studies highlight a gap in understanding when phage therapy succeeds or fails. Previous research from our team, using in vivo experiments and single-compartment mathematical models, demonstrated the synergistic clearance of acute P. aeruginosa pneumonia by phage and neutrophils despite the emergence of phage-resistant bacteria. In fact, the lung environment is highly structured, prompting the question of whether immunophage synergy explains the curative treatment of P. aeruginosa when incorporating realistic physical connectivity. To address this, we developed a metapopulation network model mimicking the lung branching structure to assess phage therapy efficacy for MDR P. aeruginosa pneumonia. The model predicts the synergistic elimination of P. aeruginosa by phage and neutrophils but emphasizes potential challenges in spatially structured environments, suggesting that higher innate immune levels may be required for successful bacterial clearance. Model simulations reveal a spatial pattern in pathogen clearance where P. aeruginosa are cleared faster at distal nodes of the bronchial tree than in primary nodes. Interestingly, image analysis of infected mice reveals a concordant and statistically significant pattern: infection intensity clears in the bottom before the top of the lungs. The combined use of modeling and image analysis supports the application of phage therapy for acute P. aeruginosa pneumonia while emphasizing potential challenges to curative success in spatially structured in vivo environments, including impaired innate immune responses and reduced phage efficacy.

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来源期刊
mSystems
mSystems Biochemistry, Genetics and Molecular Biology-Biochemistry
CiteScore
10.50
自引率
3.10%
发文量
308
审稿时长
13 weeks
期刊介绍: mSystems™ will publish preeminent work that stems from applying technologies for high-throughput analyses to achieve insights into the metabolic and regulatory systems at the scale of both the single cell and microbial communities. The scope of mSystems™ encompasses all important biological and biochemical findings drawn from analyses of large data sets, as well as new computational approaches for deriving these insights. mSystems™ will welcome submissions from researchers who focus on the microbiome, genomics, metagenomics, transcriptomics, metabolomics, proteomics, glycomics, bioinformatics, and computational microbiology. mSystems™ will provide streamlined decisions, while carrying on ASM''s tradition of rigorous peer review.
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