Oral Presentation 12th Australasian Virology Society Meeting 2024

Deficiency in gasdermin cell death proteins limits lung pathology during severe influenza virus infection (#5)

Sarah Rosli 1 2 , Christopher Harpur 1 2 , Maggie Lam 1 2 , Christopher Hodges 1 2 , Alison West 1 2 , Ashley Mansell 1 2 , Kate Lawlor 1 2 , Michelle Tate 1 2
  1. Hudson Institute of Medical Research, Clayton, VIC, Australia
  2. Molecular and Translational Sciences, Monash University, Monash University, Clayton, Victoria, Australia

Influenza A virus (IAV) has been a major global health challenge, responsible for several pandemics and recurrent annual epidemics. Despite advances in antiviral therapeutics, their effectiveness is limited by the rapid evolution of the virus. Severe IAV infections are associated with uncontrolled inflammation, lung epithelium damage and cell death. Effector cell death proteins gasdermin D (GSDMD) and gasdermin E (GSDME) mediate pyroptosis, an inflammatory and lytic type of cell death. Caspases-1 and -3 cleave GSDMD and GSDME, respectively, releasing their active N-terminal (NT) domains to form transmembrane pores. These pores facilitate the release of pro-inflammatory cytokines IL-1β and IL-18. Accumulation of these pores leads to cell lysis, releasing danger-associated molecular patterns (DAMPs), driving further inflammation. Although GSDMD and GSDME have been implicated in various inflammatory diseases, their role in IAV infection was not well characterised.

In this study, wild-type, Gsdmd-/-, or Gsdme-/- mice were intranasally infected with 104 PFU of HKx31 (H3N2) IAV, and viral loads, inflammation, cell death, and lung pathology were examined. IAV infection promoted the activation of GSDMD and GSDME cleavage in the lung of wild-type mice at days 3 and 5 post-infection. Cleaved GSDMD and GSDME co-localised with E-cadherin+ epithelial cells, while cleaved GSDME was also found in CD45+ leukocytes. Mice lacking GSDMD or GSDME displayed reduced clinical disease scores and improved survival. Notably, GSDMD and GSDME deficiency limited viral loads, neutrophil infiltration, and lung pathology, including epithelial damage and cell death. GDSMD deficiency broadly decreased a range of cytokines and chemokines in the airways. In contrast, Gsdme-/- mice showed lower levels of key cytokines IL-6 and IL-1β in the airways, as well as reduced IL-6 and TNF in the serum. Together, these findings suggest pyroptotic effectors play a detrimental role during IAV infection. Inhibiting gasdermins could offer a novel host-targeted therapeutic strategy for influenza.