Grant: Operating Grant

The Influenza virus has caused four pandemics over the past 100 years, one of which we are facing at present (A/H1N1/2009) with a weakened antiviral arsenal. Only oseltamivir (Tamiflu) and zanamivir (Relenza) are effective against the current strain, and resistant strains have already emerged. As highlighted during these events, but even during seasonal epidemics, influenza has the potential to become a deadly disease especially in those with underlying conditions. Infection with past pandemic strains of influenza (ex. H1N1/1918) as well as H5N1 avian influenza infections in humans have been associated with a rapidly progressing respiratory illness akin to severe respiratory distress syndrome which often leads to death. In both humans and animal, infection with these viruses has been associated with excessive inflammation. We propose that targeting and controlling these processes in the infected individual will lead to a better disease outcome and significantly improved survival of complicated influenza. Our research aims at showing that the activation of receptors called PPARs located in the nucleus of cells can reduce the production of inflammatory molecules. Our preliminary results show that animals treated with PPAR activators after the onset of severe infection had a significantly improved survival rate compared to non-treated animals. In addition, our study aims at determining the exact molecular events that are beneficially altered by the treatments. We will also determine how the treatments modulate innate and adaptive immunity. Our research has the potential to lead to discoveries that will identify novel mechanisms through which inflammation and cytokine production can be controlled during severe influenza (and possibility other) infection and thus lead to recovery. This is particularly important for pandemic preparedness since approved drugs that target the PPAR pathways (a class of drugs used treat type 2 diabetes) are already available on the market.