Human Neutrophils Use Different Mechanisms To Kill Aspergillus fumigatus Conidia and Hyphae: Evidence from Phagocyte Defects

Roel P Gazendam, John L van Hamme, Anton T J Tool, Mark Hoogenboezem, J Merlijn van den Berg, Jan M Prins, Ljubomir Vitkov, Frank L. van de Veerdonk, Timo K van den Berg, Dirk Roos, Taco W. Kuijpers

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Neutrophils are known to play a pivotal role in the host defense against Aspergillus infections. This is illustrated by the prevalence of Aspergillus infections in patients with neutropenia or phagocyte functional defects, such as chronic granulomatous disease. However, the mechanisms by which human neutrophils recognize and kill Aspergillus are poorly understood. In this work, we have studied in detail which neutrophil functions, including neutrophil extracellular trap (NET) formation, are involved in the killing of Aspergillus fumigatus conidia and hyphae, using neutrophils from patients with well-defined genetic immunodeficiencies. Recognition of conidia involves integrin CD11b/CD18 (and not dectin-1), which triggers a PI3K-dependent nonoxidative intracellular mechanism of killing. When the conidia escape from early killing and germinate, the extracellular destruction of the Aspergillus hyphae needs opsonization by Abs and involves predominantly recognition via Fcγ receptors, signaling via Syk, PI3K, and protein kinase C to trigger the production of toxic reactive oxygen metabolites by the NADPH oxidase and myeloperoxidase. A. fumigatus induces NET formation; however, NETs did not contribute to A. fumigatus killing. Thus, our findings reveal distinct killing mechanisms of Aspergillus conidia and hyphae by human neutrophils, leading to a comprehensive insight in the innate antifungal response.

Original languageEnglish
Pages (from-to)1272-83
Number of pages12
JournalJournal of Immunology
Volume196
Issue number3
DOIs
Publication statusPublished - 1 Feb 2016

Cite this

Gazendam, R. P., van Hamme, J. L., Tool, A. T. J., Hoogenboezem, M., van den Berg, J. M., Prins, J. M., ... Kuijpers, T. W. (2016). Human Neutrophils Use Different Mechanisms To Kill Aspergillus fumigatus Conidia and Hyphae: Evidence from Phagocyte Defects. Journal of Immunology, 196(3), 1272-83. https://doi.org/10.4049/jimmunol.1501811