title: Decreased Cell Wall Galactosaminogalactan in Aspergillus nidulans Mediates Dysregulated Inflammation in the Chronic Granulomatous Disease Host.
abstract: Invasive aspergillosis is a major threat to patients suffering from impaired neutrophil function, with Aspergillus fumigatus being the most common species causing this life-threatening condition. Patients with chronic granulomatous disease (CGD) not only develop infections with A. fumigatus, but also exhibit a unique susceptibility to infection with the normally nonpathogenic species Aspergillus nidulans. In this study, we compared the inflammatory cytokine response of peripheral blood mononuclear cells (PBMCs) from healthy and CGD patients to these two fungal species. CGD patients displayed evidence for a chronic hyperinflammatory state as indicated by elevated plasma IL-1β and TNF-α levels. PBMCs isolated from CGD patients secreted higher levels of IL-1β and TNF-α in response to A. nidulans as compared with A. fumigatus. The presence or absence of melanin in the cell wall of A. nidulans did not alter the cytokine release by healthy or CGD PBMCs. In contrast, A. fumigatus mutants lacking melanin stimulated higher levels of proinflammatory cytokine release from healthy, but not CGD PBMCs. Purified cell wall polysaccharides of A. nidulans induced a much higher level of IL-1β secretion by CGD PBMCs than did cell wall polysaccharides isolated from A. fumigatus. Using modified A. nidulans strains overexpressing galactosaminogalactan, we were able to show that the increased secretion of inflammatory cytokines by CGD PBMCs in response to A. nidulans are a consequence of low levels of cell wall-associated galactosaminogalactan in this species.
authors.affiliation: 1 Department of Pediatrics, Radboud University Medical Center , Nijmegen, The Netherlands .
authors.forename: Stefanie S V
authors.initials: SS
authors.lastname: Henriet
authors.affiliation: 2 Department of Medical Microbiology and Infectious Diseases, Erasmus MC, University Medical Center Rotterdam , Rotterdam, The Netherlands .
authors.forename: Wendy W J
authors.initials: WW
authors.lastname: van de Sande
authors.affiliation: 3 Departments of Medicine, Microbiology and Immunology, McGill University , Montreal, Canada .
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Lee
authors.affiliation: 1 Department of Pediatrics, Radboud University Medical Center , Nijmegen, The Netherlands .
authors.forename: Elles
authors.initials: E
authors.lastname: Simonetti
authors.affiliation: 4 Plant Biology Department, University of Georgia , Athens, Georgia .
authors.forename: Michelle
authors.initials: M
authors.lastname: Momany
authors.affiliation: 5 Department of Medical Microbiology, Radboud University Medical Center , Nijmegen, The Netherlands .
authors.forename: Paul E
authors.initials: PE
authors.lastname: Verweij
authors.affiliation: 5 Department of Medical Microbiology, Radboud University Medical Center , Nijmegen, The Netherlands .
authors.forename: Antonius J M M
authors.initials: AJ
authors.lastname: Rijs
authors.affiliation: 1 Department of Pediatrics, Radboud University Medical Center , Nijmegen, The Netherlands .
authors.forename: Gerben
authors.initials: G
authors.lastname: Ferwerda
authors.affiliation: 3 Departments of Medicine, Microbiology and Immunology, McGill University , Montreal, Canada .
authors.forename: Donald C
authors.initials: DC
authors.lastname: Sheppard
authors.affiliation: 1 Department of Pediatrics, Radboud University Medical Center , Nijmegen, The Netherlands .
authors.forename: Marien I
authors.initials: MI
authors.lastname: de Jonge
authors.affiliation: 1 Department of Pediatrics, Radboud University Medical Center , Nijmegen, The Netherlands .|6 Aberdeen Fungal Group, Institute of Medical Sciences, University of Aberdeen , Aberdeen, United Kingdom .
authors.forename: Adilia
authors.initials: A
authors.lastname: Warris
mesh_terms: D001233:Aspergillus nidulans / Q000378:metabolism*; D015415:Biomarkers; D016022:Case-Control Studies; D002473:Cell Wall / Q000378:metabolism*; D016207:Cytokines / Q000097:blood / Q000378:metabolism; D006105:Granulomatous Disease, Chronic / Q000276:immunology / Q000378:metabolism / Q000382:microbiology* / Q000473:pathology; D054884:Host-Pathogen Interactions; D006801:Humans; D018836:Inflammation Mediators / Q000097:blood / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000276:immunology / Q000378:metabolism; D008543:Melanins / Q000378:metabolism / Q000494:pharmacology; D011134:Polysaccharides / Q000378:metabolism*
chemical_list: D015415:Biomarkers; D016207:Cytokines; D018836:Inflammation Mediators; D053583:Interleukin-1beta; D008543:Melanins; D011134:Polysaccharides; C062157:galactosaminogalactan