Inflammation and Redox Biology in Pneumonia

Over the course of a lifetime, the average person will experience hundreds of respiratory infections, with the greatest susceptibility occurring at early and advanced ages. While for most individuals, symptoms will remain mild, these infections can induce significant morbidity and mortality across the global population. Acute respiratory infections account for thousands of hospitalizations and billions in associated healthcare costs in the United States alone. Understanding the mechanisms behind why some individuals will require additional care and others remain relatively asymptomatic could lead to a reduction of overall mortality and reduced economic burden for individuals and the healthcare system. A common complication of respiratory viral infection is secondary bacterial pneumonia, which exacerbates symptoms and increases mortality risk. Current best practice is empiric treatment with antibiotics upon admission to the hospital. With the continued rise of multidrug-resistant bacteria, there is a dire need to generate new therapeutic options and understand mechanisms behind the increased susceptibility to secondary bacterial pneumonia to reduce the antibiotic burden and improve patient outcomes. Additionally, there are currently few antiviral drugs approved for treatment of respiratory viral infection, and those that are, have narrow windows of effectiveness. The focus of this dissertation is on new methods of predicting respiratory infection etiology and severity within the highly susceptible pediatric population. Using blood biomarkers of inflammation, we can identify those individuals likely to require prolonged care. We could also use these biomarkers to distinguish between confirmed viral or community acquired pneumonia (CAP) cases. In a mouse model of severe respiratory viral-bacterial infection we assessed potential mechanisms of viral-induced secondary bacterial pneumonia through modulation of redox biology and surveyed pharmacological modulators to determine their potential as therapeutic options. These studies highlight that measurable blood inflammatory responses could be used to determine those patients who will require additional care in response to infection, and that modulation of pathways within the inflammatory response could be useful therapeutics.