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.

Public Health 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 recently introduced antifungal drugs makes it urgent to develop new therapeutics, in particular those targeting the host immune response. The proposed project will develop and use advanced mathematical and computational tools, calibrated to extensive experimental data, in order to explore new potential therapeutic targets to treat this disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI135128-02
Application #
9733114
Study Section
Modeling and Analysis of Biological Systems Study Section (MABS)
Program Officer
Love, Dona
Project Start
2018-07-01
Project End
2023-06-30
Budget Start
2019-07-01
Budget End
2020-06-30
Support Year
2
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Connecticut
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
022254226
City
Farmington
State
CT
Country
United States
Zip Code
06030