Introduction: IAV causes a significant burden and has limited effective therapies due to rapid viral mutation. Our in vitro pilot studies demonstrated HDCA6 plays a novel protective role in IAV infection via activating the IAV-sensing DDX1 complex and subsequent induction of antiviral interferon responses and inhibition of NFKβ- and NLRP3-mediated pro-inflammatory factors. The role of HDAC6 in in vivo infection has not been defined.

Aim: To assess the role and therapeutic potential of HDAC6 in protecting against IAV infection and associated disease in vivo.

Methods and Results: Wild-type, C57BL/6 mice were treated with recombinant (r)HDAC6 prior to IAV infection (PR8/H1N1). The effects of rHDAC6 on IAV titre and immune cell influx in bronchoalveolar lavage fluid (BALF), antiviral and pro-inflammatory responses in lung tissue, lung pathology and lung function were assessed at 3 and 7 days post infection (dpi). rHDAC6 reduced IAV titre compared to sham-treated controls (3dpi, 7dpi). rHDAC6 treatment protects against IAV-induced weight loss (5-7dpi) and lung pathology (7dpi) and reduces IAV-induced baseline transpulmonary resistance (3dpi, 7dpi). The protective effects of rHDAC6 are associated with increased production of type I and III IFNs (3dpi, 7dpi) and suppression of pro-inflammatory factors interleukin IL1β, TNFα, IL6 and KC (3dpi) and decreased neutrophil infiltration (3dpi, 7dpi).

Conclusion: Our findings show that HDAC6 plays a novel protective role in IAV infection by boosting innate antiviral responses and inhibiting pro-inflammatory signalling. We have shown for the first time that rHDAC6 is effective at treating IAV infection and disease in vivo.