Decreased Cell Wall Galactosaminogalactan in Aspergillus nidulans Mediates Dysregulated Inflammation in the Chronic Granulomatous Disease Host
SourceJournal of Interferon and Cytokine Research, 36, 8, (2016), pp. 488-498
Article / Letter to editor
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Paediatrics - OUD tm 2017
Journal of Interferon and Cytokine Research
SubjectRadboudumc 4: lnfectious Diseases and Global Health RIMLS: Radboud Institute for Molecular Life Sciences
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-1beta and TNF-alpha levels. PBMCs isolated from CGD patients secreted higher levels of IL-1beta and TNF-alpha 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-1beta 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.
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