Multiscale modeling of the battle over iron in invasive lung infection

项目总结 侵袭性曲霉病是免疫功能低下的宿主中最常见的真菌感染之一，并携带 糟糕的结果。致病微生物烟曲霉的孢子普遍分布在 环境。健康的宿主清除吸入的孢子不会发展成疾病，但受损的人 免疫力容易受到一种危及生命的呼吸道感染的影响，这种感染随后可以传播到其他器官。 越来越多的免疫抑制疗法在移植和癌症中的使用已经显著增加。 这种感染带来的痛苦和死亡，预计这一趋势将继续下去。当前的治疗方法 主要集中在病原体上，但对寄主防御的组成部分有更好的了解 这种感染可能导致针对这种感染的新疗法的开发，可能是联合治疗。 使用抗真菌药物。 铁对所有生物都是必不可少的，而限制铁的可获得性是 抗菌宿主对许多微生物的防御；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起来。 例如，在治疗方面，使用增强宿主铁隔离机制的药物。这个 该项目的总体目标是开发一个可用作模拟的多尺度数学模型 铁在侵袭性曲霉病中作用的工具。该模型将在分子尺度上整合机制。 通过组织级别的事件和全身秤捕捉到肝脏的作用。该项目带来了创新的 研究这种感染的方法，并通过一个 新颖的模块化软件设计，可提高灵活性、再现性和模型共享。

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.