Withdrawn 9th Australasian Vaccines & Immunotherapeutics Development Meeting 2022

Silencing pulmonary sensory neurons increases influenza disease severity (#113)

Nathalie A.J. Verzele 1 2 , Matthew W. Trewella 2 , Stuart B. Mazzone 2 , Kirsty R. Short 1 , Alice E. McGovern 2
  1. School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, Queensland, Australia
  2. Department of Anatomy and Physiology, The University of Melbourne, Melbourne, Victoria, Australia

Background: During influenza A virus (IAV) infection, the driver of disease severity is often an aberrant inflammatory response with various cell types contributing to the pathogenesis. The lungs are densely innervated by pulmonary sensory neurons, critical for monitoring the environment within the airways and lungs. We recently showed that during IAV respiratory viral infection these pulmonary sensory neurons undergo transcriptional changes and take on an antiviral inflammatory phenotype, characterized by increased expression of Irf9. However, to date, the pulmonary sensory neurons have not been investigated as a potential therapeutic target in IAV infections.

Methods: In a murine model (C57B6/J mice) of IAV respiratory infection (Auckland/1/09 H1N1), disease pathogenesis was compared with and without inhibiting pulmonary sensory neuron activity through daily treatment with QX-314 (300µM by nebulisation)charged sodium channel inhibitor. The role of IAV-induced upregulated vagal ganglia Irf9 expression was assessed in disease pathogenesis by knocking down ganglia expression using targeted delivery of an adeno-associated viral vector encoding Irf9 short hairpin RNA (AAV-IRF9shRNA). Pathogenesis was measured using whole body plethysmography, clinical scoring, ganglia gene expression, viral titre and immune cell infiltration into the lungs and ganglia.

Results: QX-314 treated animals demonstrated more severe weight loss and increased severity of clinical symptoms compared to vehicle treated IAV infected mice. This was accompanied by increased lung total cell counts, with a decrease in CD8+ T-cells. In the vagal ganglia, IAV-induced Irf9 expression was significantly lower in QX-314 treated animals compared to vehicle treated controls. IAV-infected AAV-IRF9shRNA animals similarly presented with increased clinical symptoms and functional measures of increased airflow obstruction compared to blank vector treated controls.

Conclusion: These data indicate that the vagal sensory system plays an important role in regulating IAV pathogenesis. Modulating their activity may therefore be a novel therapeutic approach to reduce the severity of respiratory viral infections.