Aspergillus species are ubiquitous environmental moulds, with spores inhaled daily by most humans. Immunocompromised hosts can develop an invasive
infection resulting in high mortality. There is, therefore, a pressing need for host-centric
therapeutics for this
infection. To address it, we created a multi-scale computational model of the
infection, focused on its interaction with the innate immune system and
iron, a critical nutrient for the pathogen. The model, parameterized using published data, was found to recapitulate a wide range of biological features and was experimentally validated in vivo. Conidial swelling was identified as critical in fungal strains with high growth, whereas the
siderophore secretion rate seems to be an essential prerequisite for the establishment of the
infection in low-growth strains. In immunocompetent hosts, high growth, high swelling probability and impaired leucocyte activation lead to a high conidial germination rate. Similarly, in neutropenic hosts, high fungal growth was achieved through synergy between high growth rate, high swelling probability, slow leucocyte activation and high
siderophore secretion. In summary, the model reveals a small set of parameters related to fungal growth,
iron acquisition and leucocyte activation as critical determinants of the fate of the
infection.