Computational Modeling of Macrophage Iron Sequestration during Host Defense against Aspergillus.
Computational Modeling of Macrophage Iron Sequestration during Host Defense against Aspergillus.
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作者：
铁对曲霉的毒力是必不可少的，而限制铁的利用是抗菌宿主防御的关键机制。被招募到感染部位的巨噬细胞是这一过程的关键，它使用多种交叉机制来协调病原体的铁隔离。为了全面了解这在曲霉病中是如何实现的，我们生成了一个人单核细胞来源的巨噬细胞对曲霉菌的反应的转录时间序列，并利用这一时间序列和现有的文献构建了一个在这种感染过程中巨噬细胞对铁的处理的机制计算模型。我们发现巨噬细胞在暴露于真菌后2~4 h开始出现压倒性的反应，包括铁输入蛋白转铁蛋白受体-1、二价金属转运蛋白-1和ZIP家族转运蛋白的转录上调，以及铁出口蛋白铁转运蛋白的转录下调。该计算模型基于离散动力系统框架，由21个三态节点组成，并用模型生成中未使用的附加实验数据进行了验证。该模型准确地捕捉了大多数定量测量节点的稳态和轨迹。在实验数据中，我们惊讶地发现转铁蛋白受体-1上调先于炎性细胞因子的诱导，这一特征与模型预测背道而驰。模型模拟表明，真菌识别后直接诱导转铁蛋白受体1(TfR1)，独立于铁调节蛋白-不稳定铁池(IRP-LIP)系统，解释了这一发现。我们期望这一模型将有助于定量理解铁调节作为曲霉病基本宿主防御机制的作用。尽管有最好的治疗方法，侵袭性肺曲霉菌病仍是免疫抑制患者死亡的主要原因。在这种感染中，剥夺病原体的铁是宿主防御的重要组成部分，但宿主实现这一目标的机制是复杂的。为了了解招募的巨噬细胞如何在感染过程中调节铁缺乏，我们开发并验证了一个机制计算模型，该模型整合了该领域的现有信息。这种方法提供的见解可以帮助设计铁调节疗法作为抗真菌治疗。
Iron is essential to the virulence of Aspergillus species, and restricting iron availability is a critical mechanism of antimicrobial host defense. Macrophages recruited to the site of infection are at the crux of this process, employing multiple intersecting mechanisms to orchestrate iron sequestration from pathogens. To gain an integrated understanding of how this is achieved in aspergillosis, we generated a transcriptomic time series of the response of human monocyte-derived macrophages to Aspergillus and used this and the available literature to construct a mechanistic computational model of iron handling of macrophages during this infection. We found an overwhelming macrophage response beginning 2 to 4 h after exposure to the fungus, which included upregulated transcription of iron import proteins transferrin receptor-1, divalent metal transporter-1, and ZIP family transporters, and downregulated transcription of the iron exporter ferroportin. The computational model, based on a discrete dynamical systems framework, consisted of 21 3-state nodes, and was validated with additional experimental data that were not used in model generation. The model accurately captures the steady state and the trajectories of most of the quantitatively measured nodes. In the experimental data, we surprisingly found that transferrin receptor-1 upregulation preceded the induction of inflammatory cytokines, a feature that deviated from model predictions. Model simulations suggested that direct induction of transferrin receptor-1 (TfR1) after fungal recognition, independent of the iron regulatory protein-labile iron pool (IRP-LIP) system, explains this finding. We anticipate that this model will contribute to a quantitative understanding of iron regulation as a fundamental host defense mechanism during aspergillosis. IMPORTANCE Invasive pulmonary aspergillosis is a major cause of death among immunosuppressed individuals despite the best available therapy. Depriving the pathogen of iron is an essential component of host defense in this infection, but the mechanisms by which the host achieves this are complex. To understand how recruited macrophages mediate iron deprivation during the infection, we developed and validated a mechanistic computational model that integrates the available information in the field. The insights provided by this approach can help in designing iron modulation therapies as anti-fungal treatments.
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