The Role of the IL-22/IL-22R Axis in the Lung following Influenza Infection.
Description
Influenza is a highly contagious viral respiratory infection that occurs in annual outbreaks. Activity levels for the 2017-2018 influenza season reached heights not seen since the 2009 pandemic. This was partly due to the inefficiency of the vaccine (25% effective) against the predominant circulating strain, H3N2. To make matters worse, current antiviral therapies must be given within 48 hours of the onset of symptoms. This is often well outside the window of opportunity for hospitalized patients. Developing a therapy that promotes repair of the extensive damage that occurs in severely infected patients is vital for their recovery. Our lab focuses on the innate immune response, more specifically the IL-22 pathway, and the mechanisms involved in repair following pulmonary injury and infection. IL-22 is important in cell proliferation, wound healing, maintaining epithelial barriers and innate pathogen defense. In the lung, its receptor, IL-22Ra1, is only found on epithelial cells and is rapidly induced in response to damage of the lung epithelium. The central hypothesis of this dissertation is that IL-22Ra1 is induced during influenza infection on pulmonary epithelial and progenitor cells, allowing for enhanced sensitivity to IL-22. We have found this induction to be TLR3 and STAT1 dependent. In vivo, bronchial brushings from H1N1 infected mice (PR/8/34) mice demonstrate that Il-22ra1 is rapidly induced in the airways following infection. This occurs in a STAT1 dependent manner as upregulation does not occur in STAT1-/- mice in vivo or following STAT1 inhibition in vitro. This pathway is important as IL-22 treatment induces expression of tight junction transcripts both in vitro and in vivo. Moreover, we believe this induction of IL-22Ra1 is critical for the survival of lung progenitor cells as we have data showing that over 80% of basal cells express Il-22ra1 in the naïve lung. Furthermore, we have developed a lung organoid model and upon treatment with IL-22, organoid size was significantly increased after seven days as evidenced by measurement and BrdU incorporation. Overall, our data shows that IL-22Ra1 is highly induced after injury and subsequent treatment with IL-22 is essential for altering tight junctions and promoting lung repair.