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 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.