Two independent killing mechanisms of Candida albicans by human neutrophils: evidence from innate immunity defects

Invasive fungal infections, accompanied by high rates of mortality, represent an increasing problem in medicine. Neutrophils are the major effector immune cells in fungal killing. Based on studies with neutrophils from patients with defined genetic defects, we provide evidence that human neutrophils...

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Published in:	Blood Vol. 124; no. 4; pp. 590 - 597
Main Authors:	Gazendam, Roel P., van Hamme, John L., Tool, AntonT.J., van Houdt, Michel, Verkuijlen, PaulJ.J.H., Herbst, Martin, Liese, Johannes G., van de Veerdonk, Frank L., Roos, Dirk, van den Berg, Timo K., Kuijpers, Taco W.
Format:	Journal Article
Language:	English
Published:	United States Elsevier Inc 24-07-2014
Subjects:	Candida albicans - growth & development Candida albicans - immunology Candidiasis - immunology Candidiasis - microbiology Candidiasis - prevention & control Cells, Cultured Humans Immunity, Innate - immunology Intracellular Signaling Peptides and Proteins - metabolism Lectins, C-Type - antagonists & inhibitors Lectins, C-Type - genetics Lectins, C-Type - metabolism NADPH Oxidases - antagonists & inhibitors NADPH Oxidases - genetics NADPH Oxidases - metabolism Neutrophils - immunology Phagocytosis Protein Kinase C - antagonists & inhibitors Protein Kinase C - genetics Protein Kinase C - metabolism Protein-Tyrosine Kinases - metabolism Reactive Oxygen Species - metabolism Receptors, IgG - antagonists & inhibitors Receptors, IgG - genetics Receptors, IgG - metabolism Syk Kinase
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Summary:	Invasive fungal infections, accompanied by high rates of mortality, represent an increasing problem in medicine. Neutrophils are the major effector immune cells in fungal killing. Based on studies with neutrophils from patients with defined genetic defects, we provide evidence that human neutrophils use 2 distinct and independent phagolysosomal mechanisms to kill Candida albicans. The first mechanism for the killing of unopsonized C albicans was found to be dependent on complement receptor 3 (CR3) and the signaling proteins phosphatidylinositol-3-kinase and caspase recruitment domain-containing protein 9 (CARD9), but was independent of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity. The second mechanism for the killing of opsonized C albicans was strictly dependent on Fcγ receptors, protein kinase C (PKC), and reactive oxygen species production by the NADPH oxidase system. Each of the 2 pathways of Candida killing required Syk tyrosine kinase activity, but dectin-1 was dispensable for both of them. These data provide an explanation for the variable clinical presentation of fungal infection in patients suffering from different immune defects, including dectin-1 deficiency, CARD9 deficiency, or chronic granulomatous disease. •Human neutrophils use 2 independent mechanisms for the killing of unopsonized and serum-opsonized C albicans.•Unopsonized Candida killing depends on CR3 and CARD9 but not dectin-1; opsonized Candida killing on FcγR, PKC, and NADPH oxidase activity.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0006-4971 1528-0020
DOI:	10.1182/blood-2014-01-551473