Poster Presentation 14th Lorne Infection and Immunity 2024

Gasdermin D deficiency limits the severity of pulmonary disease during influenza A virus infection (#132)

Sarah Rosli 1 2 , Christopher Harpur 1 2 , Maggie Lam 1 2 , Alison West 1 2 , Christopher Hodges 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 the potential to cause yet another pandemic. We urgently need new therapies for severe IAV infections, as current antiviral drugs have been reported to be ineffective, particularly due to the increase in antiviral drug resistance. Dysregulated host responses to IAV infection contribute to hyperinflammation, which promotes adverse and irreversible lung pathology. IAV infection of host cells activates several pattern recognition receptors, including the NLRP3 inflammasome, which releases proinflammatory cytokines and ultimately cell death. Gasdermin D (GSDMD) is an executioner of a lytic form of cell death called pyroptosis.  Cleavage of GSDMD prompts its bioactive N-terminal GSDMD (NT-GSDMD) domain to create a transmembrane pore, which has been shown to promote the cellular release of pro-inflammatory cytokines including IL-1β and IL-18, as well as danger-associated molecular patterns (DAMPs), promoting further inflammation. While GSDMD has been implicated in many inflammatory diseases, its role in IAV infection was not well characterised. In this study, we investigated the role of GSDMD in modulating the severity of IAV-induced lung pathology. Cleaved GSDMD was upregulated in vivo in the lung epithelial cells at day 3 post-IAV infection. Mice lacking GSDMD (Gsdmd-/-) were less susceptible to HKx31 (H3N2) IAV infection, displaying significantly improved survival in comparison to wild-type controls. Gsdmd-/- mice displayed less severe pulmonary pathology, including epithelial damage and cell death. Further, the bronchoalveolar lavage fluid of Gsdmd-/- mice presented with a significant reduction in total cellularity, which correlated with fewer numbers of infiltrating neutrophils and neutrophil chemoattractants, MIP-2/CXCL2 and KC/CXCL1, at days 3 and 5 post-infection. This was also accompanied by a significant decrease in pro-inflammatory cytokines, including CCL2/MCP-1, IL-6, and TNF at day 3. Interestingly, the number of infectious viral particles in lung tissue was reduced on day 3. Together, these results suggest that the absence of GSDMD limits the severity of IAV infection. Inhibition of GSDMD may provide a novel host-targeted IAV therapeutic strategy that limits the development of fatal lung disease.