title: Hypoxia-inducible factor 1α modulates metabolic activity and cytokine release in anti-Aspergillus fumigatus immune responses initiated by human dendritic cells.
abstract: The mold Aspergillus fumigatus causes life-threatening infections in immunocompromised patients. Over the past decade, new findings in research have improved our understanding of A. fumigatus-host interactions, including the recent identification of myeloid-expressed hypoxia-inducible factor 1α (HIF-1α) as a relevant immune-modulating transcription factor and potential therapeutic target in anti-fungal defense. However, the function of HIF-1α signaling for human anti-A. fumigatus immunity is still poorly understood, including its role in dendritic cells (DCs), which are important regulators of anti-fungal immunity. This study investigated the functional relevance of HIF-1α in the anti-A. fumigatus immune response initiated by human DCs. Hypoxic cell culture conditions were included because hypoxic microenvironments occur during A. fumigatus infections and may influence the host immune response. HIF-1α was stabilized in DCs following stimulation with A. fumigatus under normoxic and hypoxic conditions. This stabilization was partially dependent on dectin-1, the major receptor for A. fumigatus on human DCs. Using siRNA-based HIF-1α silencing combined with genome-wide transcriptional analysis, a modulatory effect of HIF-1α on the anti-fungal immune response of human DCs was identified. Specifically, the difference in the transcriptomes of HIF-1α silenced and non-silenced DCs indicated that HIF-1α contributes to DC metabolism and cytokine release in response to A. fumigatus under normoxic as well as hypoxic conditions. This was confirmed by further down-stream analyses that included metabolite analysis and cytokine profiling of a time-course infection experiment. Thereby, this study revealed a so far undescribed functional relevance of HIF-1α in human DC responses against A. fumigatus.
authors.affiliation: Medical Clinic and Polyclinic II, University Hospital, 97080 Wuerzburg, Germany.
authors.forename: Mirjam
authors.initials: M
authors.lastname: Fliesser
authors.affiliation: University of Western Sydney, School of Science and Health, Campbelltown, NSW 2560, Australia.
authors.forename: Charles Oliver
authors.initials: CO
authors.lastname: Morton
authors.affiliation: Microarray Facility, University Hospital, 72076 Tuebingen, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Bonin
authors.affiliation: Institute for Infectious Diseases and Zoonoses, Ludwigs Maximilians University, 80336 Munich, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Ebel
authors.affiliation: Septomics Research Centre, Friedrich Schiller University and Leibniz Institute for Natural Product Research and Infection Biology - Hans Knoell Institute, 07745 Jena, Germany.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Hünniger
authors.affiliation: Septomics Research Centre, Friedrich Schiller University and Leibniz Institute for Natural Product Research and Infection Biology - Hans Knoell Institute, 07745 Jena, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Kurzai
authors.affiliation: Medical Clinic and Polyclinic II, University Hospital, 97080 Wuerzburg, Germany.
authors.forename: Hermann
authors.initials: H
authors.lastname: Einsele
authors.affiliation: Medical Clinic and Polyclinic II, University Hospital, 97080 Wuerzburg, Germany. Electronic address: loeffler_j@ukw.de.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Löffler
mesh_terms: D001232:Aspergillus fumigatus / Q000276:immunology*; D015687:Cell Hypoxia; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism*; D003713:Dendritic Cells / Q000276:immunology* / Q000382:microbiology*; D020869:Gene Expression Profiling; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*
chemical_list: D016207:Cytokines; D051795:Hypoxia-Inducible Factor 1, alpha Subunit
keywords: Aspergillus fumigatus; Dendritic cells; Hypoxia inducible factor 1α; Immune response; Invasive pulmonary aspergillosis