Disulfiram blocks inflammasome activation and curtails pulmonary vascular leakage in severe influenza infection
Presentation Time: 11:30 AM - 12:45 PM
Poster Board Number: B577
Abstract ID: 4976
Presenting Author:
Henry Gong , Graduate Student Research Assistant at Michigan Med., Univ. of Michigan, Lieutenant Colonel Charles S. Kettles VA Med. Ctr.
Abstract:
Introduction: Influenza is a leading cause of morbidity and mortality globally, killing up to 650,000 people annually. Severe infections are often associated with excess inflammation leading to vascular permeability and respiratory failure. We hypothesized that disulfiram (DSF) would confer beneficial immunomodulatory effects during influenza by blocking the pore-forming activity of gasdermin D following inflammasome activation.
Method: Mice were infected with H1N1 influenza A virus (20 PFU, IT) and treated daily with DSF (10mg/kg, IP) or vehicle starting 1 day pre-infection. On day 7, bronchoalveolar lavage fluid (BALF) was collected and lung leukocytes analyzed by flow cytometry. Neutrophils were isolated from bone marrow for functional assays.
Results: DSF ameliorates vascular leakage as measured by IgM in the BALF (p=0.001). No differences were seen in lung leukocyte populations, suggesting DSF may alter cell-intrinsic phenotypes. DSF reduced expression of the inflammasome activator P2X7R in lung neutrophils (p=0.03) but not in macrophages (p=0.30). We demonstrate DSF directly inhibits the release of neutrophil extracellular traps from PMA-stimulated neutrophils ex vivo (p=0.008).
Conclusion: Neutrophils are known to drive immunopathologic responses in many acute viral lung infections but there are almost no therapies available that specifically regulate their responses. DSF is an FDA-approved drug that may provide new therapeutic options for severe influenza infection.
Disulfiram blocks inflammasome activation and curtails pulmonary vascular leakage in severe influenza infection
Category
Poster and Podium (Block Symposium)