Multiscale modeling of the battle over iron in invasive lung infection
Funding: National Institute of Allergy and Infectious Diseases 1R01AI135128-01
Abstract: 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.
Modular design of multiscale models, with an application to the innate immune response to fungal respiratory pathogens
Funding: National Institute of Biomedical Imaging and Bioengineering 1U01EB024501-01, National Science Foundation EAGER #1750183
Abstract: Increased availability of biomedical data sets across spatial and temporal scales makes it possible to calibrate complex models that capture integrated processes from the molecular to the whole organism level. This complexity poses multiple challenges related to mathematical modeling, software design, validation, reproducibility, and extensibility. Visualization of model features and dynamics is a key factor in the usability of models by domain experts, such as experimental biologists and clinicians. The proposed project addresses these challenges in the context of the immune response to an important respiratory fungal infection. Its goal is to develop a novel modular approach to model architecture, using a recently introduced technology of lightweight virtual machines and our user-friendly open-source platform for the construction and linking of these so-called “Docker containers” to create complex modular models in a transparent fashion. A key benefit of software containers is that they can encompass the entire computational environment of a model, enabling unprecedented reproducibility of computational results. The overarching computational goal is to develop a novel approach to the modular design of multiscale models. While broadly applicable, this novel computational modeling approach will be focused on the development of a multiscale model capturing the early stages of invasive aspergillosis, an important health problem. Invasive aspergillosis is one of the most common fungal infections in immunocompromised hosts and carries a poor prognosis. 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. In particular, restricting iron availability is a critical mechanism of antimicrobial host defense; conversely, successful pathogens have evolved potent mechanisms for scavenging iron from the host. These mechanisms have the potential to be harnessed therapeutically. The biological focus of the proposed project is the battle over iron between the fungus and the host. The overarching biomedical goal is to develop a simulation tool to explore the role of iron in invasive aspergillosis across biochemical and biophysical conditions.
