Impaired killing of Candida albicans by granulocytes mobilized for transfusion purposes: a role for granule components

Roel P Gazendam, Annemarie van de Geer, John L van Hamme, Anton T J Tool, Dieke J van Rees, Cathelijn E M Aarts, Maartje van den Biggelaar, Floris van Alphen, Paul Verkuijlen, Alexander B Meijer, Hans Janssen, Dirk Roos, Timo K van den Berg, Taco W. Kuijpers

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Granulocyte transfusions are used to treat neutropenic patients with life-threatening bacterial or fungal infections that do not respond to anti-microbial drugs. Donor neutrophils that have been mobilized with granulocyte-colony stimulating factor (G-CSF) and dexamethasone are functional in terms of antibacterial activity, but less is known about their fungal killing capacity. We investigated the neutrophil-mediated cytotoxic response against C. albicans and A. fumigatus in detail. Whereas G-CSF/dexamethasone-mobilized neutrophils appeared less mature as compared to neutrophils from untreated controls, these cells exhibited normal ROS production by the NADPH oxidase system and an unaltered granule mobilization capacity upon stimulation. G-CSF/dexamethasone-mobilized neutrophils efficiently inhibited A. fumigatus germination and killed Aspergillus and Candida hyphae, but the killing of C. albicans yeasts was distinctly impaired. Following normal Candida phagocytosis, analysis by mass spectrometry of purified phagosomes after fusion with granules demonstrated that major constituents of the antimicrobial granule components, including major basic protein (MBP), were reduced. Purified MBP showed candidacidal activity, and neutrophil-like Crisp-Cas9 NB4-KO-MBP differentiated into phagocytes were impaired in Candida killing. Together, these findings indicate that G-CSF/dexamethasone-mobilized neutrophils for transfusion purposes have a selectively impaired capacity to kill Candida yeasts, as a consequence of an altered neutrophil granular content.

Original languageEnglish
Pages (from-to)587-96
Number of pages10
JournalHaematologica
Volume101
Issue number5
DOIs
Publication statusPublished - May 2016

Cite this

Gazendam, R. P., van de Geer, A., van Hamme, J. L., Tool, A. T. J., van Rees, D. J., Aarts, C. E. M., van den Biggelaar, M., van Alphen, F., Verkuijlen, P., Meijer, A. B., Janssen, H., Roos, D., van den Berg, T. K., & Kuijpers, T. W. (2016). Impaired killing of Candida albicans by granulocytes mobilized for transfusion purposes: a role for granule components. Haematologica, 101(5), 587-96. https://doi.org/10.3324/haematol.2015.136630