A Polysaccharide Virulence Factor from Aspergillus fumigatus Elicits Anti-inflammatory Effects through Induction of Interleukin-1 Receptor Antagonist

Abstract

The galactosaminogalactan (GAG) is a cell wall component of Aspergillus fumigatus that has potent anti-inflammatory effects in mice. However, the mechanisms responsible for the anti-inflammatory property of GAG remain to be elucidated. In the present study we used in vitro PBMC stimulation assays to demonstrate, that GAG inhibits proinflammatory T-helper (Th)1 and Th17 cytokine production in human PBMCs by inducing Interleukin-1 receptor antagonist (IL-1Ra), a potent anti-inflammatory cytokine that blocks IL-1 signalling. GAG cannot suppress human T-helper cytokine production in the presence of neutralizing antibodies against IL-1Ra. In a mouse model of invasive aspergillosis, GAG induces IL-1Ra in vivo, and the increased susceptibility to invasive aspergillosis in the presence of GAG in wild type mice is not observed in mice deficient for IL-1Ra. Additionally, we demonstrate that the capacity of GAG to induce IL-1Ra could also be used for treatment of inflammatory diseases, as GAG was able to reduce severity of an experimental model of allergic aspergillosis, and in a murine DSS-induced colitis model. In the setting of invasive aspergillosis, GAG has a significant immunomodulatory function by inducing IL-1Ra and notably IL-1Ra knockout mice are completely protected to invasive pulmonary aspergillosis. This opens new treatment strategies that target IL-1Ra in the setting of acute invasive fungal infection. However, the observation that GAG can also protect mice from allergy and colitis makes GAG or a derivative structure of GAG a potential treatment compound for IL-1 driven inflammatory diseases.

The Carbohydrate Lectin Receptor Dectin-1 Mediates the Immune Response to Exserohilum rostratum

“…For instance, Cryptococcus elaborates a dense polysaccharide capsule, which shields cell wall carbohydrates from detection by the immune system (15,16). As cell wall carbohydrates are the primary PAMPs in fungal pathogens, we focused our analysis on carbohydrates that are known or suspected to provoke an immune response in other fungal species, including mannan (17)(18)(19)(20), ␤-1,3-glucan (21-30), galactosaminogalactan (GAG) (31)(32)(33)(34)(35)(36), and chitin (37)(38)(39)(40)(41)(42)(43)(44)(45). Freshly harvested Exserohilum rostratum spores were grown in complete RPMI at 37°C with 5% CO 2 .…”

A Polysaccharide Virulence Factor of a Human Fungal Pathogen Induces Neutrophil Apoptosis via NK Cells

“…In these conditions, with whole-blood PMN activation by GG, a polysaccharide extracted from A. fumigatus, we demonstrated that NK cells are a critical trigger of PMN apoptosis. In addition, the proapoptotic effect of GG on PMNs was observed at a concentration of 20 mg/ml, which is a relevant concentration in vivo, because Aspergillus can secrete GG in a concentration of 50 mg/ml (44).…”

Differential Kinetics of Aspergillus nidulans and Aspergillus fumigatus Phagocytosis

“…GAG is an important anti-inflammatory polysaccharide of the cell wall of A. fumigatus that induces the anti-inflammatory cytokine IL-1Ra [46]. The absence of GAG in the cell wall of A. nidulans [47] may contribute to its proinflammatory capacity, yet this does not explain the additional high induction of an IL1Ra response.…”