Candida albicans Induces Metabolic Reprogramming in Human NK Cells and Responds to Perforin with a Zinc Depletion Response.

Daniela Hellwig,Maria Bouzani,Daniela Albrecht-Eckardt,Jürgen Löffler,Sascha Brunke,Michael Weber,Ronny Martin,Kerstin Hünniger,Oliver Kurzai,Jessica Voigt

doi:10.3389/fmicb.2016.00750

Abstract

As part of the innate immune system, natural killer (NK) cells are directly involved in the response to fungal infections. Perforin has been identified as the major effector molecule acting against many fungal pathogens. While several studies have shown that perforin mediated fungicidal effects can contribute to fungal clearance, neither the activation of NK cells by fungal pathogens nor the effects of perforin on fungal cells are well-understood. In a dual approach, we have studied the global gene expression pattern of primary and cytokine activated NK cells after co-incubation with Candida albicans and the transcriptomic adaptation of C. albicans to perforin exposure. NK cells responded to the fungal pathogen with an up-regulation of genes involved in immune signaling and release of cytokines. Furthermore, we observed a pronounced increase of genes involved in glycolysis and glycolysis inhibitor 2-deoxy-D-glucose impaired C. albicans induced NK cell activation. This strongly indicates that metabolic adaptation is a major part of the NK cell response to C. albicans infections. In the fungal pathogen, perforin induced a strong up-regulation of several fungal genes involved in the zinc depletion response, such as PRA1 and ZRT1. These data suggest that fungal zinc homeostasis is linked to the reaction to perforin secreted by NK cells. However, deletion mutants in PRA1 and ZRT1 did not show altered susceptibility to perforin.

Highlights

Natural killer (NK) cells are CD56+ CD3− cytotoxic lymphocytes of the innate immune system
Upon comparison of gene expression of natural killer (NK) cells confronted with C. albicans to that of mock-treated cells, a significantly higher number of genes was differentially regulated in cytokine primed NK cells, indicating a faster and more intense response compared to the primary cells (Figure 2; Supplementary Table S2)
Depletion of NK cells in T/B/NK cell-deficient mice resulted in increased susceptibility to systemic C. albicans infection, which may point to an essential contribution of NK cells in immunocompromised hosts (Quintin et al, 2014)

Summary

Introduction

Natural killer (NK) cells are CD56+ CD3− cytotoxic lymphocytes of the innate immune system. Major effector mechanisms are the release of transmembrane pore forming perforin and granzyme B or induction of death receptor-mediated apoptosis (Lanier, 2008). In addition to C. neoformans, antifungal activity of NK cells has been demonstrated for Paracoccidioides brasiliensis, Coccidioides immitis, Rhizopus arrhizus (Rhizopus oryzae), A. fumigatus and C. albicans (Jimenez and Murphy, 1984; Petkus and Baum, 1987; Bouzani et al, 2011; Schmidt et al, 2011, 2015; Voigt et al, 2014). Perforin appears to be the major mediator of anti-Candida activity in human NK cells (Voigt et al, 2014). In perforin-granzyme mediated cell death, granzyme enters the target cell via these pores and initiates apoptosis in the target cell (Voskoboinik et al, 2015)

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Conclusion