Influenza A virus (IAV) causes a significant global burden and the emergence of novel pandemic viruses is a constant threat heightened by increasing incidence of highly pathogenic avian IAV in migratory birds and poultry and cases of human transmission (e.g. H5N1, H7N9). Since seasonal vaccines are ineffective against emerging pandemic IAV strains and resistance to current licensed antivirals is easily acquired, the development of additional therapeutic strategies is required. Severe IAV infection evokes a robust inflammatory response leading to the uncontrolled production of cytokine and chemokines, leukocyte infiltration, and the release of reactive oxygen and nitrogen species. Excessive inflammation and oxidative insults to the lung result in significant neutrophil infiltration into the alveolar space, edema and hemorrhage from disrupted endothelial-epithelial cell barriers, and acute respiratory distress syndrome. Our lab discovered and synthesized novel lipid mediators (electrophilic fatty acid derivatives, EFADs) capable of broadly stabilizing inflammation through synchronously activating antioxidant responses and inhibiting inflammation. We postulate that EFADs will mitigate IAV-induced lung injury by promoting antioxidant responses and limiting inflammation. This hypothesis will be tested by pursuing two experimental aims. 1. Evaluate EFADs as therapeutics for IAV-induced lung injury 2. Determine the mechanisms of EFAD action in treating murine IAV pathogenesis This research plan combines analytical strategies including high performance liquid chromatography mass spectrometry and flow cytometry, with tools to measure lung function and the host response to viral infection. These studies will yield a better understanding of host-pathogen interactions as pertaining to oxidative stress, the innate immune response and electrophilic lipid signaling. It is anticipated that novel signaling mechanisms will be revealed for the mitigation of respiratory infection and lung injury ? laying a strong foundation for new therapeutic strategies having broad implications in global health.
Severe influenza infection leads to an excessive innate immune response that evokes a reactive inflammatory response (e.g. reactive species generation and cytokine release) that can be targeted by electrophilic fatty acid derivatives (EFADs) which manifest adaptive antioxidant and anti-inflammatory signaling capabilities. This Research Plan aims to evaluate the ability of EFADs to mitigate influenza-induced lung injury using a novel, multifaceted approach that combines the fields of free radical biology, immunology, and virology. This project will unravel connections between oxidative stress, inflammation, and antiviral responses as well as reveal novel therapeutic strategies having broad implications in global health.
| Buchan, Gregory J; Bonacci, Gustavo; Fazzari, Marco et al. (2018) Nitro-fatty acid formation and metabolism. Nitric Oxide 79:38-44 |
