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Live Imaging of Antifungal Activity by Human Primary Neutrophils and Monocytes in Response to A. fumigatus
Published on: April 19, 2017
Human Neutrophils Use Different Mechanisms To Kill Aspergillus fumigatus Conidia and Hyphae: Evidence from Phagocyte
Roel P Gazendam1, John L van Hamme2, Anton T J Tool2
1Sanquin Research and Landsteiner Laboratory, Academic Medical Center, University of Amsterdam, 1066 CX Amsterdam, the Netherlands; r.gazendam@sanquin.nl.
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.
Insights
Human neutrophils use distinct mechanisms to combat Aspergillus. Neutrophils kill Aspergillus conidia via CD11b/CD18 and intracellular pathways, while hyphae are targeted using antibody-dependent Fcγ receptor signaling and reactive oxygen metabolites.
Area of Science:
- Immunology
- Mycology
- Infectious Diseases
Background:
- Neutrophils are critical for host defense against fungal pathogens like Aspergillus.
- Understanding neutrophil interactions with Aspergillus is vital, especially in immunocompromised patients.
Purpose of the Study:
- To elucidate the specific mechanisms human neutrophils employ to recognize and eliminate Aspergillus fumigatus conidia and hyphae.
- To investigate the role of neutrophil extracellular traps (NETs) in Aspergillus killing.
Main Methods:
- Utilized neutrophils from patients with defined genetic immunodeficiencies to study Aspergillus killing.
- Investigated recognition pathways involving integrins, dectin-1, Fcγ receptors, and signaling molecules (PI3K, Syk, PKC).
- Assessed the contribution of reactive oxygen metabolites and NET formation to fungal clearance.
Main Results:
- Conidial recognition occurs via integrin CD11b/CD18, activating a PI3K-dependent nonoxidative killing mechanism.
- Hyphal destruction requires antibody opsonization and Fcγ receptor engagement, triggering reactive oxygen metabolite production.
- Neutrophil extracellular traps (NETs) are induced by Aspergillus but do not contribute to fungal killing.
Conclusions:
- Human neutrophils employ distinct strategies for killing Aspergillus conidia and hyphae.
- Identified key molecular players in neutrophil-mediated antifungal immunity, including integrins, Fcγ receptors, and oxidative burst.
- Neutrophil extracellular traps are not essential for Aspergillus clearance.
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