AUTHOR=Srivastava Mugdha , Bencurova Elena , Gupta Shishir K. , Weiss Esther , Löffler Jürgen , Dandekar Thomas 

TITLE=Aspergillus fumigatus Challenged by Human Dendritic Cells: Metabolic and Regulatory Pathway Responses Testify a Tight Battle

JOURNAL=Frontiers in Cellular and Infection Microbiology

VOLUME=Volume 9 - 2019

YEAR=2019

URL=https://www.frontiersin.org/journals/cellular-and-infection-microbiology/articles/10.3389/fcimb.2019.00168

DOI=10.3389/fcimb.2019.00168

ISSN=2235-2988

ABSTRACT=Dendritic cells (DCs) serve as a bridge between the innate and the acquired immunity. Aspergillosis is a major lethal condition in immunocompromised patients caused by the versatile saprophytic fungus Aspergillus fumigatus. While the healthy human immune system is able to ward off A. fumigatus infections in general, immune-deficient patients are highly vulnerable against invasive aspergillosis. Surviving regulated immune responses of human DCs is one of the vital processes for survival of A. fumigatus during infection. In this context, the study of metabolism defining infection elucidates the survival strategies of pathogen and immune cells. We established a metabolic model of A. fumigatus central metabolism during infection of dendritic cells 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 a crucial role of fatty acid metabolism along with other metabolic changes. The gene expression data and their analysis illuminates additional regulatory pathways activated in the DCs apart from interleukin regulation. In particular Toll-like receptor signaling pathway, NOD-like receptor signaling pathway and RIG-I-like receptor signaling pathway were significantly active. Moreover, we identified subnetworks and several novel key regulators such as UBC, EGFR and CUL3 of DCs activated in response to A. fumigatus. In conclusion, we provide an integrated picture of the metabolic and regulatory aspects of the interaction of A. fumigatus and dendritic cells during infection.