Anakinra restores the immunological misfiring that drives influenza-associated pulmonary aspergillosis

Author:

Laura Seldeslachts (BE)

Abstract:

Influenza-associated pulmonary aspergillosis (IAPA) is a severe fungal superinfection affecting critically ill patients with influenza. Despite the use of contemporary therapies with antifungal and antivirals, mortality rates remain very high. Currently, there are insufficient immunological insights into the pathogenesis of IAPA to propose an effective adjunctive immunotherapy. We aimed to investigate in a mouse model for IAPA how influenza predisposes to the development of invasive pulmonary aspergillosis.
Methods:
Immunocompetent mice were challenged with an intranasal instillation of influenza on day 0 followed by an orotracheal inoculation with Aspergillus 4 days later. Mice were monitored daily for overall health status, lung pathology with micro-computed tomography (µCT), and fungal burden with bioluminescence imaging (BLI). At the endpoint, state-of-the-art immunophenotyping, spatial transcriptomics, immunofluorescence stainings and histopathological examinations were performed.
Results:
We identified interleukin-1 (IL-1) hyperinflammation, extensive neutrophil activation, and neutrophil extracellular trap (NET) formation as signatures of IAPA (Figures 1A-1D). This hyperinflammation led to an immunological imbalance with defective neutrophil effector functions (ROS production by neutrophils, nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activation, neutrophil degranulation, antimicrobial peptide production) impairing the fungal host immune response, and to a highly permissive environment for Aspergillus to grow (Figure 1E and 1F). Blocking the IL-1 receptor with anakinra timely reduced the hyperinflammation, restored the neutrophil effector function and rescued IAPA mice from invasive pulmonary aspergillosis and death (Figure 2).
Conclusions:
Our findings underscore the key role of IL-1 hyperinflammation in the immunological misfiring that drives IAPA and suggest anakinra as a promising immunomodulatory therapy for IAPA patients.

Abstract Number: 67

Conference Year: 2024

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