Human primary myeloid dendritic cells interact with the opportunistic fungal pathogen<i>Aspergillus fumigatus</i>via the C-type lectin receptor Dectin-1

Hefter, Maike; Lother, Jasmin; Weiß, Esther; Schmitt, Anna Lena; Fliesser, Mirjam; Einsele, Hermann; Loeffler, Juergen

doi:10.1093/mmy/myw105

Cited by 16 publications

(13 citation statements)

References 24 publications

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“…Plasma βDG levels positively correlated with the frequency of activated CD4 and CD8 T cells and plasma sCD14 and negatively correlated with Dectin-1 and NKp30 expression on monocytes and NK cells, respectively. Such relationships are supported by previous findings of βDG stimulation leading to monocyte and NK cell activation as well as IL-6 and IL-8 production via Dectin-1 and NKp30, respectively [34][35][36][37]. Our study showed there was an inverse correlation between βDG levels with Dectin-1 and NKp30 expression in PLWH, demonstrating that βDG Comparison of βDG with markers of bacterial translocation, gut damage, and HIV disease progression.…”

Section: Discussionsupporting

confidence: 91%

Circulating (1→3)-β-D-glucan Is Associated With Immune Activation During Human Immunodeficiency Virus Infection

Study

Mehraj

Ramendra

et al. 2019

Clinical Infectious Diseases

124

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Background Microbial translocation from the gut to systemic circulation contributes to immune activation during human immunodeficiency virus (HIV) infection and is usually assessed by measuring plasma levels of bacterial lipopolysaccharide (LPS). Fungal colonization in the gut increases during HIV-infection and people living with HIV (PLWH) have increased plasma levels of fungal polysaccharide (1→3)-β-D-Glucan (βDG). We assessed the contribution of circulating DG to systemic immune activation in PLWH. Methods Cross-sectional and longitudinal assessments of plasma βDG levels were conducted along with markers of HIV disease progression, epithelial gut damage, bacterial translocation, proinflammatory cytokines, and βDG-specific receptor expression on monocytes and natural killer (NK) cells. Results Plasma βDG levels were elevated during early and chronic HIV infection and persisted despite long-term antiretroviral therapy (ART). βDG increased over 24 months without ART but remained unchanged after 24 months of treatment. βDG correlated negatively with CD4 T-cell count and positively with time to ART initiation, viral load, intestinal fatty acid–binding protein, LPS, and soluble LPS receptor soluble CD14 (sCD14). Elevated βDG correlated positively with indoleamine-2,3-dioxygenase-1 enzyme activity, regulatory T-cell frequency, activated CD38+Human Leukocyte Antigen - DR isotype (HLA-DR)+ CD4 and CD8 T cells and negatively with Dectin-1 and NKp30 expression on monocytes and NK cells, respectively. Conclusions PLWH have elevated plasma βDG in correlation with markers of disease progression, gut damage, bacterial translocation, and inflammation. Early ART initiation prevents further βDG increase. This fungal antigen contributes to immune activation and represents a potential therapeutic target to prevent non–acquired immunodeficiency syndrome events.

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Section: Discussionsupporting

confidence: 91%

Circulating (1→3)-β-D-glucan Is Associated With Immune Activation During Human Immunodeficiency Virus Infection

Study

Mehraj

Ramendra

et al. 2019

Clinical Infectious Diseases

124

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“…We hypothesize that downregulation of Dectin-1 exposure on human moDCs prevents severe and uncontrolled inflammatory reactions while on murine BMDCs, Dectin-1 expression is required for continuous ingestion and killing of the fungus. This is consistent with our previous data showing that anti-Dectin-1 antibody treatment of human moDCs as well as ex vivo myeloid DCs subsequently inhibited secretion of pro-inflammatory cytokines after contact with A. fumigatus, C. albicans , or zymosan ( 4 , 39 ). This is also consistent with the observation that naïve mice lacking Dectin-1 show reduced killing of conidia and a higher mortality rate than wild-type mice ( 40 ).…”

Section: Discussionsupporting

confidence: 93%

Human and Murine Innate Immune Cell Populations Display Common and Distinct Response Patterns during Their In Vitro Interaction with the Pathogenic Mold Aspergillus fumigatus

et al. 2017

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Aspergillus fumigatus is the main cause of invasive fungal infections occurring almost exclusively in immunocompromised patients. An improved understanding of the initial innate immune response is key to the development of better diagnostic tools and new treatment options. Mice are commonly used to study immune defense mechanisms during the infection of the mammalian host with A. fumigatus. However, little is known about functional differences between the human and murine immune response against this fungal pathogen. Thus, we performed a comparative functional analysis of human and murine dendritic cells (DCs), macrophages, and polymorphonuclear cells (PMNs) using standardized and reproducible working conditions, laboratory protocols, and readout assays. A. fumigatus did not provoke identical responses in murine and human immune cells but rather initiated relatively specific responses. While human DCs showed a significantly stronger upregulation of their maturation markers and major histocompatibility complex molecules and phagocytosed A. fumigatus more efficiently compared to their murine counterparts, murine PMNs and macrophages exhibited a significantly stronger release of reactive oxygen species after exposure to A. fumigatus. For all studied cell types, human and murine samples differed in their cytokine response to conidia or germ tubes of A. fumigatus. Furthermore, Dectin-1 showed inverse expression patterns on human and murine DCs after fungal stimulation. These specific differences should be carefully considered and highlight potential limitations in the transferability of murine host–pathogen interaction studies.

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“…Based on criterion 2 (constitutive expression ≥ 50 RKPM), we identified a further 13 candidate receptors, of which six were differentially regulated (criterion 3). Without exception, all six genes were down-regulated upon stimulation with β-glucans, which could possibly be explained by a need to restrict de novo protein synthesis and duration of signalling to prevent over-stimulation (60–63). Possibly, analysis of protein and/or gene expression at different time points could show up-regulation.…”

Section: Discussionmentioning

confidence: 99%

Studies Into β-Glucan Recognition in Fish Suggests a Key Role for the C-Type Lectin Pathway

et al. 2019

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Immune-modulatory effects of β-glucans are generally considered beneficial to fish health. Despite the frequent application of β-glucans in aquaculture practice, the exact receptors and downstream signalling remains to be described for fish. In mammals, Dectin-1 is a member of the C-type lectin receptor (CLR) family and the best-described receptor for β-glucans. In fish genomes, no clear homologue of Dectin-1 could be identified so far. Yet, in previous studies we could activate carp macrophages with curdlan, considered a Dectin-1-specific β-(1,3)-glucan ligand in mammals. It was therefore proposed that immune-modulatory effects of β-glucan in carp macrophages could be triggered by a member of the CLR family activating the classical CLR signalling pathway, different from Dectin-1. In the current study, we used primary macrophages of common carp to examine immune modulation by β-glucans using transcriptome analysis of RNA isolated 6 h after stimulation with two different β-glucan preparations. Pathway analysis of differentially expressed genes (DEGs) showed that both β-glucans regulate a comparable signalling pathway typical of CLR activation. Carp genome analysis identified 239 genes encoding for proteins with at least one C-type Lectin Domains (CTLD). Narrowing the search for candidate β-glucan receptors, based on the presence of a conserved glucan-binding motif, identified 13 genes encoding a WxH sugar-binding motif in their CTLD. These genes, however, were not expressed in macrophages. Instead, among the β-glucan-stimulated DEGs, a total of six CTLD-encoding genes were significantly regulated, all of which were down-regulated in carp macrophages. Several candidates had a protein architecture similar to Dectin-1, therefore potential conservation of synteny of the mammalian Dectin-1 region was investigated by mining the zebrafish genome. Partial conservation of synteny with a region on the zebrafish chromosome 16 highlighted two genes as candidate β-glucan receptor. Altogether, the regulation of a gene expression profile typical of a signalling pathway associated with CLR activation and, the identification of several candidate β-glucan receptors, suggest that immune-modulatory effects of β-glucan in carp macrophages could be a result of signalling mediated by a member of the CLR family.

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Human primary myeloid dendritic cells interact with the opportunistic fungal pathogenAspergillus fumigatusvia the C-type lectin receptor Dectin-1

Cited by 16 publications

References 24 publications

Circulating (1→3)-β-D-glucan Is Associated With Immune Activation During Human Immunodeficiency Virus Infection

Circulating (1→3)-β-D-glucan Is Associated With Immune Activation During Human Immunodeficiency Virus Infection

Human and Murine Innate Immune Cell Populations Display Common and Distinct Response Patterns during Their In Vitro Interaction with the Pathogenic Mold Aspergillus fumigatus

Studies Into β-Glucan Recognition in Fish Suggests a Key Role for the C-Type Lectin Pathway

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