Multiscale modeling of the role of heme during invasive pulmonary aspergillosis
PIs:
Borna Mehrad, MD
Reinhard Laubenbacher, PhD
Project Summary
Invasive aspergillosis is among the most common fungal infections 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, during which the fungus invades lung tissues, and can then disseminate to other organs. Aspergillosis is becoming more common and more resistant to antifungal drugs. 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. In the last funding period, we developed a multi–scale computational model of the host response to Aspergillus, and used it as a hypothesis-generating tool to guide experiments to understand mechanisms of iron acquisition during the infection. In the course of these studies, we discovered that the release of extracellular heme as a result of lung hemorrhage during invasive aspergillosis is a key mechanism that promotes fungal growth and virulence. Based on our preliminary data, this renewal application is focused on the inter-connected effects of extracellular heme on both the host and the fungus, and the effect of this on the course of the infection. In Aim 1, we will incorporate the role of heme into our existing multi-scale model of invasive pulmonary aspergillosis, and use the model to mechanistically dissect the contribution of heme to illness progression in the infection, and in Aim 2, we will determine the contribution of extracellular heme release to formation of lung neutrophil extracellular traps and the development of lung injury during invasive aspergillosis. If successful, this project will mechanistically define the central role of extracellular heme in the pathobiology of invasive aspergillosis, and serve as a paradigm for the use of mathematical modeling to integrate complex biological processes and generate rational hypotheses in order to generate new knowledge.
Relevance Statement
Invasive aspergillosis represents a major and growing health problem in the U.S. and around the world. The growing population of immunocompromised patients, combined with increased resistance to anti-fungal drugs makes it urgent to develop new therapies for this infection, in particular those targeting the host immune response. The proposed project will develop and use advanced mathematical and computational tools, together with extensive experimental data generated using in vivo murine and ex vivo human experimental infections, in order to explore new mechanisms that can be therapeutically targeted in this disease.