Blickensdorf Marco, Timme Sandra, Figge Marc Thilo
Research Group Applied Systems Biology, Leibniz Institute for Natural Product Research and Infection Biology - Hans Knöll Institute, Jena, Germany.
Faculty of Biological Sciences, Institute of Microbiology, Friedrich Schiller University Jena, Jena, Germany.
Front Microbiol. 2020 Aug 12;11:1951. doi: 10.3389/fmicb.2020.01951. eCollection 2020.
The healthy state of an organism is constantly threatened by external cues. Due to the daily inhalation of hundreds of particles and pathogens, the immune system needs to constantly accomplish the task of pathogen clearance in order to maintain this healthy state. However, infection dynamics are highly influenced by the peculiar anatomy of the human lung. Lung alveoli that are packed in alveolar sacs are interconnected by so called Pores of Kohn. Mainly due to the lack of methods, the role of Pores of Kohn in the mammalian lung is still under debate and partly contradicting hypotheses remain to be investigated. Although it was shown by electron microscopy that Pores of Kohn may serve as passageways for immune cells, their impact on the infection dynamics in the lung is still unknown under conditions. In the present study, we apply a hybrid agent-based infection model to quantitatively compare three different scenarios and discuss the importance of Pores of Kohn during infections of . is an airborne opportunistic fungus with rising incidences causing severe infections in immunocompromised patients that are associated with high mortality rates. Our hybrid agent-based model incorporates immune cell dynamics of alveolar macrophages - the resident phagocytes in the lung - as well as molecular dynamics of diffusing chemokines that attract alveolar macrophages to the site of infection. Consequently, this model allows a quantitative comparison of three different scenarios and to study the importance of Pores of Kohn. This enables us to demonstrate how passaging of alveolar macrophages and chemokine diffusion affect infection dynamics. We show that Pores of Kohn alter important infection clearance mechanisms, such as the spatial distribution of macrophages and the effect of chemokine signaling. However, despite these differences, a lack of passageways for alveolar macrophages does impede infection clearance only to a minor extend. Furthermore, we quantify the importance of recruited macrophages in comparison to resident macrophages.
生物体的健康状态不断受到外部因素的威胁。由于每天吸入数百种颗粒和病原体,免疫系统需要不断完成病原体清除任务以维持这种健康状态。然而,感染动态受到人类肺部特殊解剖结构的高度影响。包裹在肺泡囊中的肺泡通过所谓的孔氏孔相互连接。主要由于缺乏相关方法,孔氏孔在哺乳动物肺部中的作用仍存在争议,部分相互矛盾的假设有待研究。尽管电子显微镜显示孔氏孔可能作为免疫细胞的通道,但在某些条件下它们对肺部感染动态的影响仍然未知。在本研究中,我们应用基于混合代理的感染模型来定量比较三种不同情况,并讨论孔氏孔在[具体真菌名称]感染期间的重要性。[具体真菌名称]是一种空气传播的机会性真菌,发病率不断上升,会在免疫功能低下的患者中引起严重感染,且与高死亡率相关。我们基于混合代理的模型纳入了肺泡巨噬细胞(肺部的常驻吞噬细胞)的免疫细胞动态,以及吸引肺泡巨噬细胞到感染部位的趋化因子扩散的分子动态。因此,该模型允许对三种不同情况进行定量比较,并研究孔氏孔的重要性。这使我们能够证明肺泡巨噬细胞的通过和趋化因子扩散如何影响[具体真菌名称]感染动态。我们表明孔氏孔改变了重要的感染清除机制,例如巨噬细胞的空间分布和趋化因子信号传导的作用。然而,尽管存在这些差异,但肺泡巨噬细胞缺乏通道仅在较小程度上阻碍感染清除。此外,我们还定量比较了招募的巨噬细胞与常驻巨噬细胞的重要性。