Seldeslachts Laura, Kraisin Sirima, Dewi Intan M W, Feys Simon, Staels Frederik, Gkountzinopoulou Marina, Jacobs Cato, Tielemans Birger, Vanhoffelen Eliane, Reséndiz-Sharpe Agustin, De Herdt Lander, Kwan Oswin, Vandamme Niels, Roels Jana, Neumann Julika, Prezzemolo Teresa, Malengier-Devlies Bert, Stroobants Mathias, Carvalho Agostinho, Matthys Patrick, Naesens Lieve, Lagrou Katrien, Khan Mona, Mombaerts Peter, Verbeken Erik, Martinod Kimberly, Wauters Joost, van de Veerdonk Frank L, Velde Greetje Vande, Humblet-Baron Stephanie
Department of Imaging and Pathology, Biomedical MRI, KU Leuven, 3000 Leuven, Belgium.
Department of Microbiology, Immunology, and Transplantation, Laboratory for Clinical Infectious and Inflammatory Disorders, KU Leuven, 3000 Leuven, Belgium.
Sci Transl Med. 2025 Dec 3;17(827):eadw9578. doi: 10.1126/scitranslmed.adw9578.
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 . 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.
流感相关肺曲霉病（IAPA）是一种严重的真菌二重感染，影响患有流感的重症患者。目前的治疗针对致病病原体，但未解决导致发病的宿主免疫反应失调问题。宿主导向的免疫疗法可以弥补这一治疗空白。在此，我们使用患者样本和IAPA小鼠模型研究了驱动IAPA的宿主-病原体因素。我们确定白细胞介素-1（IL-1）介导的炎症、中性粒细胞活化和中性粒细胞胞外陷阱（NET）释放是IAPA发病机制的关键特征。这种炎症导致免疫失衡，中性粒细胞效应功能缺陷，包括活性氧生成（ROS）受损和烟酰胺腺嘌呤二核苷酸磷酸（NADPH）氧化酶活化受损，从而损害针对曲霉的真菌宿主免疫反应，使其进入一个允许其生长的环境。用阿那白滞素阻断IL-1受体可减轻炎症和NET释放，恢复中性粒细胞中的ROS生成，并使流感病毒感染的小鼠免于侵袭性肺曲霉病。我们的研究结果强调了IL-1驱动的炎症在导致IAPA的免疫功能失调中的关键作用，并表明阿那白滞素是一种有前景的针对IAPA患者的免疫调节疗法。
