Grant: Operating Grant

The cells which line the airways, called the epithelium, can be infected with viruses like influenza and rhinovirus causing symptoms of a 'common flu infection'. Sometimes these infections become severe and an individual is hospitalized, sometimes needing help to breathe with the help of a mechanical respirator. For example, a very high percentage of children admitted to hospital with severe influenza infection during the 2009-2010 pandemic H1N1 influenza season were asthmatic. Nearly all these patients were on some form of inhaled steroid medication. Our initial results show that steroids can enhance virus infection in the airway epithelium by activating the cell, like the virus does, during infection. Therefore, with additional cell activation by steroids the virus life cycle is helped-along by steroid assisted activation. We have begun to examine normal healthy epithelial cells from children and we have already found striking increases in the amount of infection in these cells during steroid treatment. We believe that current asthma medications like glucocorticosteroids (GCS), while excellent anti-inflammatory drugs, and enhance virus infection by pre-activating the cell. We propose two aims. Firstly, we will discover the cellular pathways that are activated in the presence of GCS. Secondly, we will characterize the consequences of GCS treatment on virus infection in epithelial cells obtained from asthmatic children and adults and compare this to the responses of epithelial cells from similarly aged non-asthmatics. Finally we will examine these responses in a mouse model of asthma. In this model, mice have been made allergic to house-dust mites making them relevant to human asthma. If our hypothesis is true, drug treatment strategies that involve GCS will have to be refined or avoided during pandemic or severe influenza seasons.