Multiscale modeling of the battle over iron in invasive lung infection

项目摘要 侵袭性曲霉病是免疫受损宿主中最常见的真菌感染之一， 可怜的结果。病原体烟曲霉的孢子普遍分布在 环境健康的宿主可以清除吸入的孢子而不发生疾病，但受损的个体 免疫系统容易受到威胁生命的呼吸道感染，然后传播到其他器官。 在移植和癌症中越来越多地使用免疫抑制疗法， 这种感染造成的痛苦和死亡，预计这一趋势将继续下去。目前的治疗方法 主要集中在病原体上，但更好地了解宿主防御的组成部分， 这种感染可能会导致开发新的治疗方法来对抗这种感染， 抗真菌药物。 铁对所有生物体都是必不可少的，限制铁的可用性是铁缺乏的关键机制。 抗微生物宿主防御许多微生物;相反，成功的病原体已经进化 从宿主体内清除铁的有效机制这些机制有可能被利用 在治疗上，例如用增强宿主的铁螯合机制的药物。的 这个项目的首要目标是开发一个多尺度的数学模型，可以作为一个模拟 铁在侵袭性曲霉病中的作用的工具。该模型将在分子尺度上整合机制 其中组织水平事件和全身尺度捕获肝脏的作用。该项目带来了一个创新的 的方法来研究这种感染，并介绍了创新的功能，多尺度建模，通过一个 新颖的模块化软件设计，提高了灵活性、可重复性和模型共享。

PROJECT SUMMARY Invasive aspergillosis is among the most common fungal infection in immunocompromised hosts and carries a poor outcome. The spores of the causative organism, Aspergillus fumigatus, are ubiquitously distributed in the environment. Healthy hosts clear the inhaled spores without developing disease, but individuals with impaired immunity are susceptible to a life-threatening respiratory infection that can then disseminate to other organs. The increasing use of immunosuppressive therapies in transplantation and cancer has dramatically increased suffering and death from this infection, and this trend is expected to continue. Current therapeutic approaches have been focused primarily on the pathogen, but a better understanding of the components of host defense in this infection may lead to the development of new treatments against this infection, possibly in combination with antifungal drugs. Iron is essential to all living organisms, and restricting iron availability is a critical mechanism of antimicrobial host defense against many microorganisms; conversely, successful pathogens have evolved potent mechanisms for scavenging iron from the host. These mechanisms have the potential to be harnessed therapeutically, for example with drugs that enhance the host’s iron sequestration mechanisms. The overarching goal of this project is to develop a multi-scale mathematical model that can serve as a simulation tool of the role of iron in invasive aspergillosis. The model will integrate mechanisms at the molecular scale with tissue-level events and a whole-body scale capturing the role of the liver. The project brings an innovative approach to the study of this infection, and introduces innovative features to multiscale modeling through a novel modular software design that improves flexibility, reproducibility, and model sharing.