Targeting metabolism to improve outcomes following severe influenza infection

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Targeting Metabolism to Improve Outcomes following Severe Influenza Infection Brydie Huckestein Advisor: Dr. John Alcorn Program in Microbiology and Immunology, University of Pittsburgh ABSTRACT Widespread epithelial damage in the lungs is a hallmark of influenza infection. Our laboratory and others have shown that influenza infected mice have persistent lung damage, inflammation, and epithelial metaplasia up to 60 days post-infection. In humans, alveolitis can persist for years following an influenza infection. I hypothesize that treating mice with metabolism-targeting medications will improve lung repair following influenza infection by reducing inflammation and promoting alveolar regeneration. Epithelial metaplasia following influenza infection reduces lung function and is caused by undifferentiated lineage negative epithelial progenitor cells (LNEPs). Preliminary data indicates LNEPs have increased activation of the energy sensing kinase mammalian target of rapamycin complex 1 (mTORC1) 21 days following influenza infection. Studies in other stem cell populations show that mTORC1 activation can inhibit differentiation into mature cell types, but its role in LNEP differentiation is unknown. I propose that treating mice with the mTORC1 inhibitor rapamycin two weeks following influenza infection will promote differentiation of LNEPs into AT II cells and reduce the presence of epithelial metaplasia. Additionally, preliminary data suggests oxidative stress is occurring in the lungs 21 days following influenza infection. Ingenuity Pathway Analysis shows that macrophage ROS production is increased in the mouse lung at this time, and high resolution respirometry data indicates increased oxidative phosphorylation. I propose that treating mice with metformin, an AMPK activator, will reduce oxidative stress during lung repair following influenza infection. The following studies will determine how rapamycin and metformin impact inflammation and cellular repair mechanisms in the lung during the recovery phase following severe influenza infection. The goal of this project is to determine if metabolism targeting medications can be repurposed to treat patients who continue to suffer after their viral respiratory infection has been cleared.