A polysaccharide virulence factor from Aspergillus fumigatus elicits anti-inflammatory effects through induction of Interleukin-1 receptor antagonist

PLoS Pathog. 2014 Mar 6;10(3):e1003936. doi: 10.1371/journal.ppat.1003936. eCollection 2014 Mar.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Aspergillosis / immunology*
  • Aspergillus fumigatus / immunology*
  • Cytokines / biosynthesis
  • Cytokines / immunology
  • Disease Models, Animal
  • Enzyme-Linked Immunosorbent Assay
  • Female
  • Fungal Polysaccharides / immunology*
  • Humans
  • Interleukin 1 Receptor Antagonist Protein / biosynthesis*
  • Interleukin 1 Receptor Antagonist Protein / immunology
  • Leukocytes, Mononuclear / immunology
  • Mice
  • Mice, Inbred BALB C
  • Mice, Knockout
  • Polysaccharides / immunology*
  • Virulence Factors / immunology*

Substances

  • Cytokines
  • Fungal Polysaccharides
  • Interleukin 1 Receptor Antagonist Protein
  • Polysaccharides
  • Virulence Factors
  • galactosaminogalactan

Grant support

FLvdV was supported by a Veni grant of the Netherlands Organization for Scientific Research, and a NCMLS grant from RUNMC. MGN was supported by a Vici grant of the Netherlands Organization for Scientific Research. LR was supported by the Specific Targeted Research Project "ALLFUN" FP7−HEALTH−2010−260338. TF and JPL were supported by grants from ESF (Fuminomics 06-RNP-132), FP7 (ALLFUN), EraNet Pathogenomics (ANR-08-PATH-009-02) Agence Nationale de la Recherche (ANR-06-EMPB-011-01), SAR was supported by a Veni grant of the Netherlands Organization for Scientific Research. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.