Decreased Cell Wall Galactosaminogalactan in Aspergillus nidulans Mediates Dysregulated Inflammation in the Chronic Granulomatous Disease Host

SSV Henriet, Wendy Laureijssen - van de Sande, MJ Lee, E Simonetti, M Momany, PE Verweij, AJMM Rijs, G Ferwerda, DC Sheppard, MI de Jonge, A Warris

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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-1 beta and TNF-alpha levels. PBMCs isolated from CGD patients secreted higher levels of IL-1 beta 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-1 beta 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.
Original languageUndefined/Unknown
Pages (from-to)488-498
Number of pages11
JournalJournal of Interferon and Cytokine Research
Volume36
Issue number8
DOIs
Publication statusPublished - 2016

Research programs

  • EMC MM-04-28-01

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