Ewald2021 - Innate immune response during invasive aspergillosis by dynamic optimization

ABSTRACT: Aspergillus fumigatus is an important human fungal pathogen and its conidia are constantly inhaled by humans. In immunocompromised individuals, conidia can grow out as hyphae that damage lung epithelium. The resulting invasive aspergillosis is associated with devastating mortality rates. Since infection is a race between the innate immune system and the outgrowth of A. fumigatus conidia, we use dynamic optimization to obtain insight into the recruitment and depletion of alveolar macrophages and neutrophils. We illustrate by modeling the active, but so far neglected, major role of alveolar epithelial cells in phagocytosis and cytokine release as well as the importance of fungal growth states for virulence. Hence, we discovered that germination speed is a key virulence trait of fungal pathogens due to the vulnerability of conidia against host defense. We proved this by linking measured germination kinetics of four Aspergillus spp. with their cytotoxicity against epithelial cells in silico and in vitro.Furthermore, we could reveal by modeling and ex vivo measurements, that epithelial cells are not only important phagocytes to clear conidia, but also potent mediators of cytokine release. In conclusion, our findings illustrate an underestimated role of epithelial cells in invasive aspergillosis. Further, our model affirms the importance of neutrophils and underlines that the role of macrophages in invasive aspergillosis remains elusive. We expect that our model will contribute to improvement of treatment protocols by focusing on the critical components of immune response to fungi but also fungal virulence.

SUBMITTER: Jan Ewald  

PROVIDER: MODEL2105110001 | BioModels | 2021-11-24

REPOSITORIES: BioModels