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Growth inhibition of Candida albicans by human polymorphonuclear neutrophils: activation by interferon-gamma and
Abstract:
This study was designed to determine whether anti-fungal activity in human polymorphonuclear neutrophils (PMN) might be under the regulation of cytokines such as tumor necrosis factor (TNF) and interferon-gamma (IFN-gamma). By using a radiolabel microassay developed in our laboratory that makes use of the incorporation of [3H]glucose into residual candida, we demonstrated that PMN were better able to inhibit Candida albicans growth in vitro than peripheral blood lymphocytes (PBL). PMN from normal volunteers added to C. albicans for 24 hr at 37 degrees C in a 96-well microplate inhibited fungal growth almost completely at the 300:1 effector/target ratio and frequently at 100:1. Significant activity was still detected at 10:1. In contrast, PBL from the same donors had less activity than PMN at all the ratios tested and lost all function at the 30:1 ratio. TNF and IFN-gamma added to the PMN/candida cultures additionally enhanced PMN to inhibit candida growth. Both cytokines effectively activated PMN down to 0.1 to 0.01 U/ml, and neither cytokine interfered directly with fungal growth, even up to 1000 U/ml. Concentrations of TNF and IFN-gamma below the level that enhanced PMN function when added together to PMN acted synergistically to significantly enhance their anti-fungal activity. Therefore, TNF and IFN-gamma which are active on lymphoid cells, also appear to have the ability to directly activate PMN, and the synergistic action of the two cytokines at low doses that may be below the toxic range may prove to be of clinical importance in protection of immunocompromised host against opportunistic infections.
Insights
Human neutrophils (PMN) effectively inhibit Candida albicans growth, with activity enhanced by tumor necrosis factor (TNF) and interferon-gamma (IFN-gamma). These cytokines synergistically boost PMN antifungal function, offering potential clinical benefits for immunocompromised patients.
Area of Science:
- Immunology
- Mycology
Background:
- Human polymorphonuclear neutrophils (PMN) and peripheral blood lymphocytes (PBL) are key immune cells.
- Cytokines like tumor necrosis factor (TNF) and interferon-gamma (IFN-gamma) are known to modulate immune responses.
Purpose of the Study:
- To investigate the anti-fungal activity of human PMN against Candida albicans.
- To determine the regulatory role of TNF and IFN-gamma on PMN anti-fungal function.
Main Methods:
- A radiolabel microassay using [3H]glucose incorporation to quantify Candida growth inhibition.
- In vitro co-culture experiments with C. albicans, human PMN, and PBL.
- Addition of varying concentrations of TNF and IFN-gamma to assess their impact on PMN activity.
Main Results:
- PMN demonstrated significantly higher anti-fungal activity against C. albicans compared to PBL at all tested effector/target ratios.
- Both TNF and IFN-gamma enhanced PMN's ability to inhibit fungal growth, with effective activation at low concentrations (0.1-0.01 U/ml).
- Synergistic anti-fungal activity was observed when TNF and IFN-gamma were combined at sub-optimal doses.
Conclusions:
- Human PMN possess potent in vitro anti-fungal activity against Candida albicans.
- TNF and IFN-gamma directly activate PMN, enhancing their anti-fungal capabilities.
- The synergistic action of TNF and IFN-gamma on PMN offers potential therapeutic strategies for opportunistic fungal infections in immunocompromised individuals.