Department of Bioinformatics, Friedrich Schiller University Jena, Jena, Germany.
Center for Scalable Data Analytics and Artificial Intelligence (ScaDS.AI), University of Leipzig, Leipzig, Germany.
PLoS Comput Biol. 2021 Dec 13;17(12):e1009645. doi: 10.1371/journal.pcbi.1009645. eCollection 2021 Dec.
Aspergillus fumigatus is an important human fungal pathogen and its conidia are constantly inhaled by humans. In immunocompromised individuals, conidia can grow out as hyphae that damage lung epithelium. The resulting invasive aspergillosis is associated with devastating mortality rates. Since infection is a race between the innate immune system and the outgrowth of A. fumigatus conidia, we use dynamic optimization to obtain insight into the recruitment and depletion of alveolar macrophages and neutrophils. Using this model, we obtain key insights into major determinants of infection outcome on host and pathogen side. On the pathogen side, we predict in silico and confirm in vitro that germination speed is an important virulence trait of fungal pathogens due to the vulnerability of conidia against host defense. On the host side, we found that epithelial cells, which have been underappreciated, play a role in fungal clearance and are potent mediators of cytokine release. Both predictions were confirmed by in vitro experiments on established cell lines as well as primary lung cells. Further, our model affirms the importance of neutrophils in invasive aspergillosis and underlines that the role of macrophages remains elusive. We expect that our model will contribute to improvement of treatment protocols by focusing on the critical components of immune response to fungi but also fungal virulence traits.
烟曲霉是一种重要的人类真菌病原体，其分生孢子会不断被人类吸入。在免疫功能低下的个体中，分生孢子可以生长为菌丝，破坏肺上皮细胞。由此产生的侵袭性曲霉病与毁灭性的死亡率相关。由于感染是固有免疫系统与烟曲霉分生孢子生长之间的竞赛，我们使用动态优化来深入了解肺泡巨噬细胞和中性粒细胞的募集和耗竭。使用该模型，我们深入了解了宿主和病原体方面感染结果的主要决定因素。在病原体方面，我们通过计算机模拟预测并在体外证实，出芽速度是真菌病原体的一个重要毒力特征，因为分生孢子易受宿主防御的影响。在宿主方面，我们发现上皮细胞在真菌清除中发挥作用，并且是细胞因子释放的有力介质，但这一观点之前一直被低估。这两个预测都通过对已建立的细胞系和原代肺细胞的体外实验得到了证实。此外，我们的模型证实了中性粒细胞在侵袭性曲霉病中的重要作用，并强调了巨噬细胞的作用仍然难以捉摸。我们希望我们的模型能够通过关注对真菌免疫反应的关键成分以及真菌毒力特征，来改善治疗方案。
