Zinc and manganese chelation by neutrophil S100A8/A9 (calprotectin) limits extracellular Aspergillus fumigatus hyphal growth and corneal infection Journal Article

   

Authors:	Clark, H. L.; Jhingran, A.; Sun, Y.; Vareechon, C.; Carrion, S. D.; Skaar, E. P.; Chazin, W. J.; Calera, J. A.; Hohl, T. M.; Pearlman, E.
Article Title:	Zinc and manganese chelation by neutrophil S100A8/A9 (calprotectin) limits extracellular Aspergillus fumigatus hyphal growth and corneal infection
Abstract:	Calprotectin, a heterodimer of S100A8 and S100A9, is an abundant neutrophil protein that possesses antimicrobial activity primarily because of its ability to chelate zinc and manganese. In the current study, we showed that neutrophils from calprotectin-deficient S100A9(-/-) mice have an impaired ability to inhibit Aspergillus fumigatus hyphal growth in vitro and in infected corneas in a murine model of fungal keratitis; however, the ability to inhibit hyphal growth was restored in S100A9(-/-) mice by injecting recombinant calprotectin. Furthermore, using recombinant calprotectin with mutations in either the Zn and Mn binding sites or the Mn binding site alone, we show that both zinc and manganese binding are necessary for calprotectin's antihyphal activity. In contrast to hyphae, we found no role for neutrophil calprotectin in uptake or killing of intracellular A. fumigatus conidia either in vitro or in a murine model of pulmonary aspergillosis. We also found that an A. fumigatus Delta zafA mutant, which demonstrates deficient zinc transport, exhibits impaired growth in infected corneas and following incubation with neutrophils or calprotectin in vitro as compared with wild-type. Collectively, these studies demonstrate a novel stage-specific susceptibility of A. fumigatus to zinc and manganese chelation by neutrophil-derived calprotectin.
Keywords:	proteins; immunity; homeostasis; superoxide; pulmonary aspergillosis; keratitis; host-defense; virulence; s100; sequestration
Journal Title:	Journal of Immunology
Volume:	196
Issue:	1
ISSN:	0022-1767
Publisher:	The American Association of Immunologists, Inc
Date Published:	2016-01-01
Start Page:	336
End Page:	344
Language:	English
ACCESSION:	WOS:000366736500036
DOI:	10.4049/jimmunol.1502037
PROVIDER:	wos
PMCID:	PMC4684987
PUBMED:	26582948
Notes:	Article -- Source: Wos

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