The use of immunosuppressive therapies for treatment of cancers, organ transplantation, has greatly exacerbated the threat posed by opportunistic pathogens. A. fumigatus is the most prevalent mould pathogen, and a frequent cause of fatal infection. In human aspergillosis severity of host damage is proportionate to the degree of immunocompromise and is worsened by an aberrant inflammatory response, which itself is provoked by pathogenic fungal growth. We apply systems and control theory to the study of epithelium infection and immune responses, and develop, in collaboration with Dr Bignell’s group at the University of Manchester and Dr Armstrong-James’ group at Imperial College London, a mathematical model of invasive aspergillosis to understand essential regulatory mechanisms which guard against tissue damage.
We introduced a dynamical systems approach to elucidate the pathogenesis of fungal infection caused by a low-dose fungal exposure (Tanaka et al. 2015), which is more physiological relevant scenario than a high-dose fungal exposure investigated in conventional animal experiments due to technical reasons. The model results capture the impact of neutrophil depletion upon fungal proliferation in high dose murine models of infection. The framework and tools developed in this project can be applied to a wide range of inflammation in epithelium and important disease challenges within respiratory, rheumatology and cardiovascular disciplines.
Our research further aims to develop in silico tools to design and optimise a clinically accepted IFNγ therapy for invasive fungal infection, by applying model predictive control. By achieving this, we will add to a toolkit available for studying IFNγ-based therapies, and take the initiative in communicating the value of a systems medicine approach.
We further apply machine learning methods to develop data-driven models to complement our mechanistic model, as well as control theoretical methods (model predictive control) to design optimal treatment regimens for individual patients.
E. Domínguez-Hüttinger, N.J. Boon, T.B. Clarke, and R.J. Tanaka.
Front. Physiol. 8:115
R. J. Tanaka, N. J. Boon, K. Vrcelj, A. Nguyen, C. Vinci, D. Armstrong-James and E. Bignell.
Scientific Reports, 5, 13958, 2015.