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Updated: Apr 27, 2026
Bio-energetics Investigation of Candida albicans Using Real-time Extracellular Flux Analysis
Published on: March 19, 2019
Two independent killing mechanisms of Candida albicans by human neutrophils: evidence from innate immunity defects
Roel P Gazendam1, John L van Hamme1, Anton T J Tool1
1Sanquin Research, and Landsteiner Laboratory, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands;
Abstract:
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.
Insights
Human neutrophils kill Candida albicans via two independent pathways. One uses complement receptor 3 (CR3) and CARD9, while the other relies on Fcγ receptors and NADPH oxidase for fungal clearance.
Area of Science:
- Immunology
- Microbiology
- Cell Biology
Background:
- Invasive fungal infections pose a significant and growing threat in medicine, often leading to high mortality rates.
- Neutrophils are critical immune cells responsible for combating fungal pathogens.
- Understanding the mechanisms of neutrophil-mediated fungal killing is crucial for managing infections.
Purpose of the Study:
- To elucidate the distinct phagolysosomal mechanisms employed by human neutrophils to eliminate Candida albicans.
- To investigate the roles of specific receptors, signaling proteins, and enzymatic activities in these killing pathways.
- To correlate these mechanisms with clinical presentations in patients with various immune deficiencies.
Main Methods:
- Utilized studies involving neutrophils from patients with specific genetic immune defects.
- Investigated the involvement of complement receptor 3 (CR3), Fcγ receptors, Syk tyrosine kinase, dectin-1, phosphatidylinositol-3-kinase, caspase recruitment domain-containing protein 9 (CARD9), protein kinase C (PKC), and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase.
- Analyzed the killing of both unopsonized and opsonized Candida albicans.
Main Results:
- Identified two independent phagolysosomal mechanisms for Candida albicans killing by neutrophils.
- The first pathway, for unopsonized fungi, depends on CR3, phosphatidylinositol-3-kinase, and CARD9, but not NADPH oxidase.
- The second pathway, for opsonized fungi, requires Fcγ receptors, PKC, and NADPH oxidase-dependent reactive oxygen species production.
- Both pathways necessitate Syk tyrosine kinase activity, while dectin-1 is dispensable.
Conclusions:
- Human neutrophils employ distinct, Syk-dependent pathways to kill Candida albicans, involving either CR3/CARD9 or FcγR/NADPH oxidase.
- These findings explain the varied clinical outcomes observed in patients with specific immune defects affecting these pathways, such as CARD9 deficiency or chronic granulomatous disease.
- The study highlights the complexity of neutrophil anti-fungal immunity and its implications for treating invasive fungal infections.
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