Interaction analyses of human monocytes co-cultured with different forms of Aspergillus fumigatus

Loeffler, Juergen; Haddad, Ziad; Bonin, Michael; Romeike, Nele; Mezger, Markus; Schumacher, Ulrike; Kapp, Markus; Gebhardt, Florian M.; Grigoleit, Goetz-Ulrich; Stevanović, Stefan; Einsele, Hermann; Hebart, Holger

doi:10.1099/jmm.0.003293-0

Cited by 52 publications

(54 citation statements)

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“…The increased expression of Th1 cytokines, IL1α , IL1β and TNF indicated a pro-inflammatory response which was consistent with previous results for A. fumigatus interacting with iDCs [13] and monocytes [11], [29]. Increased expression of IL1α , IL1β , TNF , IL8 and CCL20 was common to each interaction study.…”

Section: Resultssupporting

confidence: 91%

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The Temporal Dynamics of Differential Gene Expression in Aspergillus fumigatus Interacting with Human Immature Dendritic Cells In Vitro

et al. 2011

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Dendritic cells (DC) are the most important antigen presenting cells and play a pivotal role in host immunity to infectious agents by acting as a bridge between the innate and adaptive immune systems. Monocyte-derived immature DCs (iDC) were infected with viable resting conidia of Aspergillus fumigatus (Af293) for 12 hours at an MOI of 5; cells were sampled every three hours. RNA was extracted from both organisms at each time point and hybridised to microarrays. iDC cell death increased at 6 h in the presence of A. fumigatus which coincided with fungal germ tube emergence; >80% of conidia were associated with iDC. Over the time course A. fumigatus differentially regulated 210 genes, FunCat analysis indicated significant up-regulation of genes involved in fermentation, drug transport, pathogenesis and response to oxidative stress. Genes related to cytotoxicity were differentially regulated but the gliotoxin biosynthesis genes were down regulated over the time course, while Aspf1 was up-regulated at 9 h and 12 h. There was an up-regulation of genes in the subtelomeric regions of the genome as the interaction progressed. The genes up-regulated by iDC in the presence of A. fumigatus indicated that they were producing a pro-inflammatory response which was consistent with previous transcriptome studies of iDC interacting with A. fumigatus germ tubes. This study shows that A. fumigatus adapts to phagocytosis by iDCs by utilising genes that allow it to survive the interaction rather than just up-regulation of specific virulence genes.

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Section: Resultssupporting

confidence: 91%

“…It has been reported that IL8 is expressed in response to germ tubes of A. fumigatus [29] and the increase in IL8 production after 3 h in this study may have been due to germ tube emergence (Table 1). Furthermore, there was up-regulation of CCL20 (at 6 h–12 h of co-cultivation).…”

Section: Discussionmentioning

confidence: 54%

The Temporal Dynamics of Differential Gene Expression in Aspergillus fumigatus Interacting with Human Immature Dendritic Cells In Vitro

et al. 2011

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“…In epithelial models and direct interactions between A. fumigatus and monocytes [13], [14], dendritic cells [15], 16 and neutrophils [17] gene expression analyses have indicated the importance of a host Th1 pro-inflammatory response. The importance of a pro-inflammatory response in defense against A. fumigatus suggests a direct role for dendritic cells (DC), which act as sentries of the innate immune system [18].…”

Section: Introductionmentioning

confidence: 99%

Gene Expression Profiles of Human Dendritic Cells Interacting with Aspergillus fumigatus in a Bilayer Model of the Alveolar Epithelium/Endothelium Interface

et al. 2014

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The initial stages of the interaction between the host and Aspergillus fumigatus at the alveolar surface of the human lung are critical in the establishment of aspergillosis. Using an in vitro bilayer model of the alveolus, including both the epithelium (human lung adenocarcinoma epithelial cell line, A549) and endothelium (human pulmonary artery epithelial cells, HPAEC) on transwell membranes, it was possible to closely replicate the in vivo conditions. Two distinct sub-groups of dendritic cells (DC), monocyte-derived DC (moDC) and myeloid DC (mDC), were included in the model to examine immune responses to fungal infection at the alveolar surface. RNA in high quantity and quality was extracted from the cell layers on the transwell membrane to allow gene expression analysis using tailored custom-made microarrays, containing probes for 117 immune-relevant genes. This microarray data indicated minimal induction of immune gene expression in A549 alveolar epithelial cells in response to germ tubes of A. fumigatus. In contrast, the addition of DC to the system greatly increased the number of differentially expressed immune genes. moDC exhibited increased expression of genes including CLEC7A, CD209 and CCL18 in the absence of A. fumigatus compared to mDC. In the presence of A. fumigatus, both DC subgroups exhibited up-regulation of genes identified in previous studies as being associated with the exposure of DC to A. fumigatus and exhibiting chemotactic properties for neutrophils, including CXCL2, CXCL5, CCL20, and IL1B. This model closely approximated the human alveolus allowing for an analysis of the host pathogen interface that complements existing animal models of IA.

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“…The binding of Candida to the host’s plasmin via its surface cell receptors resulted in an increased ability to cross an in-vitro blood-brain barrier [35]. Urokinase plasminogen activator (uPA) and urokinase plasminogen activator receptor (uPAR), agents that convert plasminogen to plasmin, were up-regulated when human monocytes were co-cultured with A. fumigatus [36]. …”

Section: Resultsmentioning

confidence: 99%

Computational approaches for discovery of common immunomodulators in fungal infections: towards broad-spectrum immunotherapeutic interventions

2013

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BackgroundFungi are the second most abundant type of human pathogens. Invasive fungal pathogens are leading causes of life-threatening infections in clinical settings. Toxicity to the host and drug-resistance are two major deleterious issues associated with existing antifungal agents. Increasing a host’s tolerance and/or immunity to fungal pathogens has potential to alleviate these problems. A host’s tolerance may be improved by modulating the immune system such that it responds more rapidly and robustly in all facets, ranging from the recognition of pathogens to their clearance from the host. An understanding of biological processes and genes that are perturbed during attempted fungal exposure, colonization, and/or invasion will help guide the identification of endogenous immunomodulators and/or small molecules that activate host-immune responses such as specialized adjuvants.ResultsIn this study, we present computational techniques and approaches using publicly available transcriptional data sets, to predict immunomodulators that may act against multiple fungal pathogens. Our study analyzed data sets derived from host cells exposed to five fungal pathogens, namely, Alternaria alternata, Aspergillus fumigatus, Candida albicans, Pneumocystis jirovecii, and Stachybotrys chartarum. We observed statistically significant associations between host responses to A. fumigatus and C. albicans. Our analysis identified biological processes that were consistently perturbed by these two pathogens. These processes contained both immune response-inducing genes such as MALT1, SERPINE1, ICAM1, and IL8, and immune response-repressing genes such as DUSP8, DUSP6, and SPRED2. We hypothesize that these genes belong to a pool of common immunomodulators that can potentially be activated or suppressed (agonized or antagonized) in order to render the host more tolerant to infections caused by A. fumigatus and C. albicans.ConclusionsOur computational approaches and methodologies described here can now be applied to newly generated or expanded data sets for further elucidation of additional drug targets. Moreover, identified immunomodulators may be used to generate experimentally testable hypotheses that could help in the discovery of broad-spectrum immunotherapeutic interventions. All of our results are available at the following supplementary website: http://bioinformatics.cs.vt.edu/~murali/supplements/2013-kidane-bmc

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Interaction analyses of human monocytes co-cultured with different forms of Aspergillus fumigatus

Cited by 52 publications

References 37 publications

The Temporal Dynamics of Differential Gene Expression in Aspergillus fumigatus Interacting with Human Immature Dendritic Cells In Vitro

The Temporal Dynamics of Differential Gene Expression in Aspergillus fumigatus Interacting with Human Immature Dendritic Cells In Vitro

Gene Expression Profiles of Human Dendritic Cells Interacting with Aspergillus fumigatus in a Bilayer Model of the Alveolar Epithelium/Endothelium Interface

Computational approaches for discovery of common immunomodulators in fungal infections: towards broad-spectrum immunotherapeutic interventions

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