Anakinra restores immunological misfiring that drives influenza-associated pulmonary aspergillosis

作者：Laura Seldeslachts, Sirima Kraisin, Intan Mauli Warma Dewi, Simon Feys, Frederik Staels, Marina Gkountzinopoulou, Cato Jacobs, Birger Tielemans, Eliane Vanhoffelen, Agustin Reséndiz-Sharpe, Lander De Herdt, Oswin Kwan, Niels Vandamme, Jana Roels, Julika Neumann, Teresa Prezzemolo, Bert Malengier‐Devlies, Mathias Stroobants, Agostinho Carvalho, Patrick Matthys, Lieve Naesens, Katrien Lagrou, Mona Khan, Peter Mombaerts, Erik Verbeken, Kimberly Martinod, Joost Wauters, Frank L. van de Veerdonk, Greetje Vande Velde, Stéphanie Humblet‐Baron · 发表于：Science Translational Medicine · 年份：2025 · DOI：10.1126/scitranslmed.adw9578 · 被引用次数：6 · 研究领域：Neutrophil, Myeloperoxidase and Oxidative Mechanisms、Antifungal resistance and susceptibility、Fungal Infections and Studies

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 Aspergillus fumigatus . 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.