A Petri net model of granulomatous inflammation: implications for IL-10 mediated control of Leishmania donovani infection.
A Petri net model of granulomatous inflammation: implications for IL-10 mediated control of Leishmania donovani infection.
复制标题
DOI：
10.1371/journal.pcbi.1003334
复制
发表时间：
2013
影响因子：
4.3
通讯作者：
Kaye PM
中科院分区：
文献类型：
--
作者：
Albergante L;Timmis J;Beattie L;Kaye PM
实验性内脏利什曼病由原生动物寄生虫杜氏利什曼原虫感染小鼠引起，其特征在于肝脏中炎性细胞的局灶性积聚，形成离散的“肉芽肿”，其中寄生虫最终被消除。为了阐明肉芽肿形成和功能的基本方面，我们已经开发了一个模拟肝肉芽肿在整个感染过程中发展的计算机Petri网模型。通过与来自小鼠实验研究的数据进行比较，广泛验证了该模型，并通过灵敏度分析评估了模型的稳健性。该模型概括了在实验感染期间所观察到的疾病进展，并且还忠实地预测了肉芽肿内随时间推移所观察到的细胞组成的许多变化。通过进行计算机模拟实验，我们已经确定了一个以前不受重视的抗利什曼原虫活性的发展方面的肉芽肿间的多样性水平。此外，通过模拟IL-10基因缺陷在各种淋巴细胞和骨髓细胞群体中的影响，我们的数据表明，在肉芽肿的核心，受感染的库普弗细胞产生的IL-10的主导局部调节作用。肉芽肿性炎症是慢性感染性和非感染性疾病的共同特征。在寄生虫病内脏利什曼病中，肝脏中肉芽肿的形成是有效的细胞免疫和宿主对感染的抵抗力的标志。然而，传统的实验模型在评估这种复杂的炎症反应的动力学的能力和区分不同免疫细胞和介质对感染结果的局部贡献的能力方面具有固有的局限性。为了克服这些局限性，并提供一个未来的平台，以评估如何使用新的药物来提高宿主的耐药性，我们已经开发了一个计算模型的利什曼原虫肉芽肿。使用这个模型，我们表明，寄生虫负载的传统措施可能掩盖了一个潜在的异质性的能力，个别肉芽肿控制寄生虫的数量。此外，我们已经使用我们的模型提供了新的见解，通过肉芽肿微环境中发现的不同免疫细胞产生IL-10的相对重要性。因此，我们的模型提供了一个补充的工具，以增加对肉芽肿性炎症在这方面和其他重要的人类疾病的理解。
Experimental visceral leishmaniasis, caused by infection of mice with the protozoan parasite Leishmania donovani, is characterized by focal accumulation of inflammatory cells in the liver, forming discrete “granulomas” within which the parasite is eventually eliminated. To shed new light on fundamental aspects of granuloma formation and function, we have developed an in silico Petri net model that simulates hepatic granuloma development throughout the course of infection. The model was extensively validated by comparison with data derived from experimental studies in mice, and the model robustness was assessed by a sensitivity analysis. The model recapitulated the progression of disease as seen during experimental infection and also faithfully predicted many of the changes in cellular composition seen within granulomas over time. By conducting in silico experiments, we have identified a previously unappreciated level of inter-granuloma diversity in terms of the development of anti-leishmanial activity. Furthermore, by simulating the impact of IL-10 gene deficiency in a variety of lymphocyte and myeloid cell populations, our data suggest a dominant local regulatory role for IL-10 produced by infected Kupffer cells at the core of the granuloma. Granulomatous inflammation is a common feature of chronic infectious and non-infectious disease. In the parasitic disease visceral leishmaniasis, the formation of granulomas in the liver is a hallmark of effective cellular immunity and host resistance to infection. Conventional experimental models, however, have inherent limitations in their capacity to assess the dynamics of this complex inflammatory response and in their ability to discriminate the local contribution of different immune cells and mediators to the outcome of infection. To overcome these limitations and to provide a future platform for evaluating how novel drugs might be used to improve host resistance, we have developed a computational model of the Leishmania granuloma. Using this model, we show that conventional measures of parasite load potentially mask an underlying heterogeneity in the ability of individual granulomas to control parasite number. In addition, we have used our model to provide novel insights into the relative importance of IL-10 production by different immune cells found within the granuloma microenvironment. Our model thus provides a complementary tool to increase understanding of granulomatous inflammation in this and other important human diseases.