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- Title
Dynamic optimization reveals alveolar epithelial cells as key mediators of host defense in invasive aspergillosis.
- Authors
Ewald, Jan; Rivieccio, Flora; Radosa, Lukáš; Schuster, Stefan; Brakhage, Axel A.; Kaleta, Christoph
- 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. Using this model, we obtain key insights into major determinants of infection outcome on host and pathogen side. On the pathogen side, we predict in silico and confirm in vitro that germination speed is an important virulence trait of fungal pathogens due to the vulnerability of conidia against host defense. On the host side, we found that epithelial cells, which have been underappreciated, play a role in fungal clearance and are potent mediators of cytokine release. Both predictions were confirmed by in vitro experiments on established cell lines as well as primary lung cells. Further, our model affirms the importance of neutrophils in invasive aspergillosis and underlines that the role of macrophages 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 traits. Author summary: Fungal infections are an increasing problem and threat for individuals which suffer from an impairment of immune functions due to immunosuppressive therapies or diseases. In those patients the innate immune response is not able to efficiently clear fungal cells from body surfaces and stop an invasive growth into tissues and bloodstream infections. Aspergillus fumigatus is a ubiquitous mold as well as potent pathogen causing life-threatening infections, invasive aspergillosis, via lung inhalation of fungal spores (conidia). The innate immune response against conidia in the lung alveoli is a highly dynamic process and involves the interplay of immune cells like macrophages and neutrophils as well as lung epithelial cells. In the presented study, we used the mathematical approach of dynamic optimization to understand the roles of human cells and virulence factors of A. fumigatus in a quantitative and time-resolved manner. Our model predicts that lung epithelial cells play an important role in fungal clearance and contribute to pro-inflammatory signaling by cytokine release upon conidial stimulation. Further, this so far underappreciated role of epithelial cells and other findings are supported by experiments with established cell lines and primary lung cells of mice as model host organism.
- Subjects
EPITHELIAL cells; FUNGAL spores; ALVEOLAR macrophages; LUNGS; FUNGAL virulence; LUNG infections; PULMONARY aspergillosis; MYCOSES
- Publication
PLoS Computational Biology, 2021, Vol 17, Issue 12, p1
- ISSN
1553-734X
- Publication type
Article
- DOI
10.1371/journal.pcbi.1009645