A computational model of invasive aspergillosis in the lung and the role of iron.
A computational model of invasive aspergillosis in the lung and the role of iron.
复制标题
DOI：
10.1186/s12918-016-0275-2
复制
发表时间：
2016-04-21
影响因子：
--
通讯作者：
Laubenbacher R
中科院分区：
文献类型：
--
作者：
Oremland M;Michels KR;Bettina AM;Lawrence C;Mehrad B;Laubenbacher R
侵袭性曲霉病是免疫功能低下宿主的严重感染，由吸入无处不在的曲霉属环境霉菌的孢子引起。这种感染中的先天免疫应答需要多个募集和驻留细胞群体之间以及与真菌细胞之间的一系列复杂和相互关联的相互作用;特别是，铁对真菌生长至关重要。侵袭性曲霉菌病的计算模型在这里，该模型可以被用来作为一个合理的假设生成工具来调查主机对这种感染的反应。使用实验室数据和已发表文献的组合，生成肺组织切片的计算机模拟模型，包括肺泡管、相邻毛细血管和周围肺实质。三维代理为基础的模型集成的时间事件在真菌细胞，上皮细胞，单核细胞，和中性粒细胞吸入孢子后，在组织水平的细胞动力学，包括先天免疫反应的一部分。血液和组织中的铁水平在真菌的生长能力中起着关键作用，该模型包括不同类型细胞的铁募集和消耗。参数敏感性分析表明，该模型对于未经验证的参数是稳健的，因此是一种可行的工具，用于侵袭性曲霉病的计算机研究。使用实验室数据从侵袭性曲霉菌病的小鼠模型的背景下，短暂的中性粒细胞减少症作为验证，该模型预测定性相似的时间过程中的真菌负荷，单核细胞和中性粒细胞群体，和组织铁水平的变化。该模型为建立曲霉菌免疫反应的多尺度动态数学模型奠定了基础。本文的在线版本（doi：10.1186/s12918-016-0275-2）包含补充材料，可供授权用户使用。
Invasive aspergillosis is a severe infection of immunocompromised hosts, caused by the inhalation of the spores of the ubiquitous environmental molds of the Aspergillus genus. The innate immune response in this infection entails a series of complex and inter-related interactions between multiple recruited and resident cell populations with each other and with the fungal cell; in particular, iron is critical for fungal growth. A computational model of invasive aspergillosis is presented here; the model can be used as a rational hypothesis-generating tool to investigate host responses to this infection. Using a combination of laboratory data and published literature, an in silico model of a section of lung tissue was generated that includes an alveolar duct, adjacent capillaries, and surrounding lung parenchyma. The three-dimensional agent-based model integrates temporal events in fungal cells, epithelial cells, monocytes, and neutrophils after inhalation of spores with cellular dynamics at the tissue level, comprising part of the innate immune response. Iron levels in the blood and tissue play a key role in the fungus’ ability to grow, and the model includes iron recruitment and consumption by the different types of cells included. Parameter sensitivity analysis suggests the model is robust with respect to unvalidated parameters, and thus is a viable tool for an in silico investigation of invasive aspergillosis. Using laboratory data from a mouse model of invasive aspergillosis in the context of transient neutropenia as validation, the model predicted qualitatively similar time course changes in fungal burden, monocyte and neutrophil populations, and tissue iron levels. This model lays the groundwork for a multi-scale dynamic mathematical model of the immune response to Aspergillus species. The online version of this article (doi:10.1186/s12918-016-0275-2) contains supplementary material, which is available to authorized users.