Anakinra restores immunological misfiring that drives influenza-associated pulmonary aspergillosis

Influenza-associated pulmonary aspergillosis (IAPA) is a severe fungal superinfection affecting critically ill patients with influenza. Current treatments target the causative pathogens but do not address the dysregulated host immune responses that drive morbidity. Host-directed immunotherapies could overcome this treatment gap. Here, we studied the host-pathogen factors driving IAPA using patient samples and an IAPA mouse model. We identified interleukin-1 (IL-1)-mediated inflammation, neutrophil activation, and neutrophil extracellular trap (NET) release as crucial features in IAPA pathogenesis. This inflammation led to an immunological imbalance with defective neutrophil effector functions, including impaired reactive oxygen production (ROS) and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activation, thereby impairing the fungal host immune response toward a permissive environment for <i>Aspergillus fumigatus</i>. Blocking the IL-1 receptor with anakinra reduced inflammation and NET release, restored ROS production in neutrophils, and rescued influenza virus-infected mice from invasive pulmonary aspergillosis. Our findings underscore the crucial role of IL-1-driven inflammation in the immunological misfiring that drives IAPA and suggest anakinra as a promising immunomodulatory therapy for patients with IAPA.

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Publication Details

Journal
Science Translational Medicine
Published
2025-12-03
DOI
https://doi.org/10.1126/scitranslmed.adw9578
Primary Topic
Neutrophil, Myeloperoxidase and Oxidative Mechanisms
Type
article
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article

Anakinra restores immunological misfiring that drives influenza-associated pulmonary aspergillosis

Stéphanie Humblet‐Baron, Niels Vandamme, Marina Gkountzinopoulou, Eliane Vanhoffelen et al.
Science Translational Medicine
Neutrophil, Myeloperoxidase and Oxidative Mechanisms
article

Anakinra restores immunological misfiring that drives influenza-associated pulmonary aspergillosis

Stéphanie Humblet‐Baron, Niels Vandamme, Marina Gkountzinopoulou, Eliane Vanhoffelen, Intan Mauli Warma Dewi, Agustin Reséndiz-Sharpe, Peter Mombaerts, Bert Malengier‐Devlies, Joost Wauters, Frederik Staels, Jana Roels, Birger Tielemans, Greetje Vande Velde, Teresa Prezzemolo, Katrien Lagrou, Patrick Matthys, Frank L. van de Veerdonk, Julika Neumann, Simon Feys, Lieve M. J. Naesens, Agostinho Carvalho, Sirima Kraisin, Lander De Herdt, Laura Seldeslachts, Kimberly Martinod, Mona Khan, Mathias Stroobants, Erik Verbeken, Cato Jacobs, Oswin Kwan
article en

Abstract

Influenza-associated pulmonary aspergillosis (IAPA) is a severe fungal superinfection affecting critically ill patients with influenza. Current treatments target the causative pathogens but do not address the dysregulated host immune responses that drive morbidity. Host-directed immunotherapies could overcome this treatment gap. Here, we studied the host-pathogen factors driving IAPA using patient samples and an IAPA mouse model. We identified interleukin-1 (IL-1)-mediated inflammation, neutrophil activation, and neutrophil extracellular trap (NET) release as crucial features in IAPA pathogenesis. This inflammation led to an immunological imbalance with defective neutrophil effector functions, including impaired reactive oxygen production (ROS) and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activation, thereby impairing the fungal host immune response toward a permissive environment for <i>Aspergillus fumigatus</i>. Blocking the IL-1 receptor with anakinra reduced inflammation and NET release, restored ROS production in neutrophils, and rescued influenza virus-infected mice from invasive pulmonary aspergillosis. Our findings underscore the crucial role of IL-1-driven inflammation in the immunological misfiring that drives IAPA and suggest anakinra as a promising immunomodulatory therapy for patients with IAPA.

Science Translational MedicineVol. 17(827)
University of Crete (GR), Radboud University Nijmegen (NL), Rega Institute for Medical Research (BE), University Medical Center (US), Radboud University Medical Center (NL), VIB-KU Leuven Center for Cancer Biology (BE), MRC Centre for Regenerative Medicine (GB), VIB-KU Leuven Center for Microbiology (BE), MRC Centre for Reproductive Health (GB), Institute of Molecular Biology and Biotechnology (BG), Max Planck Research Unit for Neurogenetics (DE), Centre for Inflammation Research (GB), VIB-KU Leuven Center for Brain & Disease Research (BE), University of Rochester (US), Foundation for Research and Technology Hellas (GR), Padjadjaran University (ID), KU Leuven (BE), University of Minho (PT)
Openalex Percentile: Top 57%
Neutrophil, Myeloperoxidase and Oxidative Mechanisms
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