Role of myeloid-derived suppressor cells in pathogenic fungal infections

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dc.contributor.advisor Hartl, Dominik (Prof. Dr.) Singh, Anurag 2015-06-10T09:34:53Z 2015-06-10T09:34:53Z 2015-06
dc.identifier.other 433671009 de_DE
dc.identifier.uri de_DE
dc.description.abstract Myeloid-derived suppressor cells (MDSCs) have been characterized in cancer patients and tumor bearing mice based on their ability to suppress T-cell responses. Some recent studies also showed the impact of MDSC mediated immunomodulation during bacterial infections. However their role in infectious fungal diseases has not been described yet. Although, healthy individuals are also continuously exposed to fungi during their daily activities for example by inhaling fungal spores, they do not develop any pro-inflammatory anti-fungal immune responses. The underlying mechanisms for this tolerance are incompletely understood. We hypothesized that fungal infections induce MDSCs that modulate disease outcome. We used a set of different methods that included in vitro studies, in vivo mouse models, and human patients to demonstrate that the human-pathogenic fungi Aspergillus fumigatus and Candida albicans induce a distinct subset of neutrophilic myeloid-derived suppressor cells (MDSCs), which were able to functionally suppress. We analyzed the effect of the human-pathogenic fungi A. fumigatus and C. albicans on immune cells and noticed the expansion of a distinct cell population that was based on lineage markers and side-scatter granularity. Functionally, fungi-induced myeloid cells strongly suppressed CD4+ and CD8+ T cell proliferation in a dose-dependent manner which defines MDSCs. In addition to regulating adaptive immunity, fungi-induced MDSCs also suppressed innate natural killer (NK) cell responses. To assess whether fungi induce a similar cell population in vivo, we quantified MDSCs in healthy controls and patients with fungal infections and challenged mice with A. fumigatus or C. albicans. Both approaches demonstrated that MDSCs accumulated in infected patients and mice. Fungi-induced MDSCs expressed neutrophilic markers in both human and mice (human: CD11b+CD66b+CD14-, mice: CD11b+Ly6G+) resembling neutrophilic MDSCs as described previously. Further in vitro studies using blocking agents, immunodeficient patient samples and knockout mouse models showed that pathogenic fungi induced neutrophilic MDSCs through the pattern recognition receptor Dectin-1 and its downstream adaptor protein CARD9. We further analyzed the mechanism underlying fungal MDSC induction, and found that it was dependent on reactive oxygen species (ROS) production and involved Caspase-8 activity and interleukin-1. Furthermore, we used a murine model to assess the impact of MDSCs during systemic candidiasis and pulmonary aspergillosis in vivo. After the adoptive transfer of bone marrow-derived neutrophilic MDSCs from healthy mice to the invasive C. albicans model, recipient mice showed better health conditions and increased survival rate. This protective effect of MDSCs was not present in A. fumigatus infection model. In summary, these studies uncover a new innate immune mechanism by which pathogenic fungi regulate host defence by inducing neutrophilic MDSCs, suggesting that this mechanism might play a broader and very important role in balancing inflammation during host-pathogen interactions. These findings also define a novel regulatory role of MDSCs during fungal infections, which might be clinically relevant in developing novel immunotherapeutic strategies for patients. en
dc.language.iso en de_DE
dc.publisher Universität Tübingen de_DE
dc.rights ubt-podok de_DE
dc.rights.uri de_DE
dc.rights.uri en
dc.subject.classification Pilze , Infektion , Immunologie de_DE
dc.subject.ddc 500 de_DE
dc.subject.ddc 570 de_DE
dc.title Role of myeloid-derived suppressor cells in pathogenic fungal infections en
dc.type Dissertation de_DE
dcterms.dateAccepted 2015-05-08
utue.publikation.fachbereich Biologie de_DE
utue.publikation.fakultaet 7 Mathematisch-Naturwissenschaftliche Fakultät de_DE


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