Abstract
Dendritic cells (DCs) are antigen presenting cells which serve as a passage between the innate and the acquired immunity. Aspergillosis is a major lethal condition in immunocompromised patients caused by the adaptable saprophytic fungus Aspergillus fumigatus. The healthy human immune system is capable to ward off A. fumigatus infections however immune-deficient patients are highly vulnerable to invasive aspergillosis. A. fumigatus can persist during infection due to its ability to survive the immune response of human DCs. Therefore, the study of the metabolism specific to the context of infection may allow us to gain insight into the adaptation strategies of both the pathogen and the immune cells. We established a metabolic model of A. fumigatus central metabolism during infection of DCs and calculated the metabolic pathway (elementary modes; EMs). Transcriptome data were used to identify pathways activated when A. fumigatus is challenged with DCs. In particular, amino acid metabolic pathways, alternative carbon metabolic pathways and stress regulating enzymes were found to be active. Metabolic flux modeling identified further active enzymes such as alcohol dehydrogenase, inositol oxygenase and GTP cyclohydrolase participating in different stress responses in A. fumigatus. These were further validated by qRT-PCR from RNA extracted under these different conditions. For DCs, we outlined the activation of metabolic pathways in response to the confrontation with A. fumigatus. We found the fatty acid metabolism plays a crucial role, along with other metabolic changes. The gene expression data and their analysis illuminate additional regulatory pathways activated in the DCs apart from interleukin regulation. In particular, Toll-like receptor signaling, NOD-like receptor signaling and RIG-I-like receptor signaling were active pathways. Moreover, we identified subnetworks and several novel key regulators such as UBC, EGFR, and CUL3 of DCs to be activated in response to A. fumigatus. In conclusion, we analyze the metabolic and regulatory responses of A. fumigatus and DCs when confronted with each other.
Highlights
Aspergillus fumigatus is an airborne fungal pathogen which can cause a hypersensitive reaction, mucosal colonization, and even life-threatening invasive infection in the immunocompromised host
Our Starting Hypothesis was that the infection environment and the Dendritic cells (DCs) challenge is a strong, sometimes deadly challenge for A. fumigatus
As we go over the analysis flow and the detailed results we can see that both hypotheses were step by step replaced by novel insights on a number of specific metabolic responses in pathogen and host and these in turn were mediated by regulatory changes for which again several key players could be identified
Summary
Aspergillus fumigatus is an airborne fungal pathogen which can cause a hypersensitive reaction, mucosal colonization, and even life-threatening invasive infection in the immunocompromised host (van de Veerdonk et al, 2017). As the number of intensive care units rises, bone marrow transplantations as well as acute leukemia cases with impaired immunity rise. Virulence traits for this fungus involve non-classical and immune evasion pathways (Amich and Krappmann, 2012). The inhaled conidia are removed by the cillii of the respiratory epithelium; the smaller conidia avoid this defense and enter the respiratory tract of lungs to be further attacked by alveolar macrophages, dendritic cells (DCs), and other activated leukocytes. If conidia escape they germinate to form hyphae and invade the lung and other organs.
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