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A Polysaccharide Virulence Factor from Aspergillus fumigatus Elicits Anti-inflammatory Effects through Induction of Interleukin-1 Receptor Antagonist
- Source :
- PLoS Pathogens, PLoS Pathogens, Public Library of Science, 2014, 10 (3), pp.e1003936. ⟨10.1371/journal.ppat.1003936⟩, Plos Pathogens, 10, e1003936, Plos Pathogens, 10, 3, pp. e1003936, PLoS Pathogens, 2014, 10 (3), pp.e1003936. ⟨10.1371/journal.ppat.1003936⟩, PLoS Pathogens, Vol 10, Iss 3, p e1003936 (2014)
- Publication Year :
- 2014
- Publisher :
- Public Library of Science, 2014.
-
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.<br />Author Summary Aspergillus fumigatus is an opportunistic pathogenic fungus that primarily causes infections in the immunocompromised host. It is known that Aspergillus employs various strategies to evade immune recognition by the host's immune system. Recently, galactosaminogalactan (GAG), a new component of the Aspergillus cell wall, was discovered to have potent anti-inflammatory effects in mice making them more susceptible to Aspergillosis. In the current study we found that this anti-inflammatory property of GAG was due to its capacity to induce the potent anti-inflammatory cytokine interleukin-1 Receptor antagonist. This cytokine interferes with IL-1 signalling and thereby can reduce IL-1–induced immune responses such as T-cell responses. We also found that the induction of this anti-inflammatory cytokine by GAG correlates with increased fungal burden, and mice deficient for this cytokine were protected against aspergillosis. Additionally, we show that the capacity of GAG to induce the natural regulator of IL-1 signalling could be used in the treatment of IL-1–mediated disease such as allergy and colitis. Our study provides new insights on the immunoregulatory activity of GAG and opens up possibilities to exploit the anti-inflammatory potential of GAG as a therapy for inflammatory diseases.
- Subjects :
- medicine.medical_treatment
viruses
Galactosaminogalactan
lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4]
Pathogenesis
Aspergillosis
MESH: Mice, Knockout
Biochemistry
Aspergillus fumigatus
MESH: Fungal Polysaccharides
chemistry.chemical_compound
Mice
MESH: Animals
lcsh:QH301-705.5
[SDV.MP.MYC]Life Sciences [q-bio]/Microbiology and Parasitology/Mycology
Mice, Knockout
MESH: Cytokines
Mice, Inbred BALB C
biology
MESH: Enzyme-Linked Immunosorbent Assay
Receptor antagonist
3. Good health
MESH: Interleukin 1 Receptor Antagonist Protein
MESH: Leukocytes, Mononuclear
Cytokine
Infectious Diseases
Medical Microbiology
Medicine
Cytokines
Female
MESH: Aspergillus fumigatus
Inflammatory diseases Radboud Institute for Molecular Life Sciences [Radboudumc 5]
Research Article
lcsh:Immunologic diseases. Allergy
medicine.drug_class
Virulence Factors
Immunology
MESH: Mice, Inbred BALB C
Enzyme-Linked Immunosorbent Assay
[SDV.BC]Life Sciences [q-bio]/Cellular Biology
Mycology
Microbiology
Proinflammatory cytokine
Immune system
Polysaccharides
Virology
Genetics
medicine
Animals
Humans
MESH: Aspergillosis
Molecular Biology
MESH: Mice
Biology
MESH: Virulence Factors
MESH: Humans
Fungal Polysaccharides
biology.organism_classification
medicine.disease
Disease Models, Animal
Interleukin 1 Receptor Antagonist Protein
Interleukin 1 receptor antagonist
MESH: Polysaccharides
lcsh:Biology (General)
chemistry
Leukocytes, Mononuclear
Parasitology
MESH: Disease Models, Animal
lcsh:RC581-607
MESH: Female
Subjects
Details
- Language :
- English
- ISSN :
- 15537374 and 15537366
- Volume :
- 10
- Issue :
- 3
- Database :
- OpenAIRE
- Journal :
- PLoS Pathogens
- Accession number :
- edsair.doi.dedup.....ffbd69632c64d8186d7122405a470684