Investigation of Neonatal Influenza Pathogenesis

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DESCRIPTION (provided by applicant): Dr. Carey is a Neonatologist and has a dual appointment as an Assistant Professor of Pediatrics and Microbiology/Immunology at Drexel University College of Medicine. Her current investigative efforts are directed towards elucidating the pathogenic mechanisms underlying morbidity and mortality of respiratory viral infections in the preterm infant. Neonates face one of the highest rates of mortality and morbidity from infection. According to the World Health Organization, 3.7 million neonates younger than 28 days of age died in 2010, and 37% of these deaths were due to infectious causes1. Specifically, influenza infection leads to many hospitalizations and deaths each year, mainly in children and the elderly. There are little data on why neonates exhibit increased mortality to influenza virus, although we know they do not have the mature, full immune repertoire that adults have at their disposal. In order to investigate this increased mortality, we have established a clinically-relevant model of neonatal influenza virus infection in 3-day old neonatal mice. We hope to elucidate mechanisms of increased pathogenesis in order to develop therapeutic interventions for an extremely vulnerable, but understudied, population. In our preliminary work, we determined that when 3-day old mice are infected with influenza, there is a high rate of death, approaching 80% by 8 days post infection. The amount of virus in the pup's lungs is higher immediately after infection as compared to adults. This early loss of viral control cannot be attributed to viral- specific T-cell immunity, as it is prior to the period when adults or neonates mount an immunodominant viral- specific CD8+ T-cell response in the lungs. This suggests that the lung innate host response in neonates is qualitatively different from that of adults. By using our novel neonatal mouse model, we are proposing studies to determine the critical differences in how the neonatal mice respond to influenza virus infection. As we investigate the situation further, we propose two research goals: 1) Determine differences in gene activation in infected neonatal mouse lung cells versus adult mouse lung cells. By using a novel recombinant Influenza virus that expresses Green Fluorescent Protein (PR8-GFP) and transcriptome analysis by Next Generation Sequencing of RNA (RNAseq), we will examine whether neonatal lung epithelial cells and alveolar macrophages respond differently to infection with influenza virus than adult cells. 2) Determine whether providing a probiotic will help protect neonatal mice from influenza infection. Based on its effects on adult respiratory infection, we hypothesize that microbiome colonization with probiotics like Lactobacillus can alter immunity to respiratory viral infection and may serve as a potential therapy to help either prevent or diminish the pathogenesis of respiratory viral infections in infants. However, up to this point, there have not been investigations into the use of intranasal probiotics for respiratory infections in infants. Attaining more knowledge of neonatal immune responses is essential if we are to develop effective vaccines or therapeutics against influenza virus or other respiratory viruses. This knowledge may allow us to develop novel therapeutic strategies against viral respiratory infections that reduce morbidity and mortality in neonates. This research proposal represents a critical step in attaining the candidate's long-term goal: to transition to an independent research career focused on mechanistic studies of respiratory viral pathogenesis in the preterm infant. In addition to the proposed research, Dr. Carey has formulated a multi- pronged training plan, including: didactic courses, scientific meetings, clinical service, and a superb mentoring team. This plan will build her skills in biostatistics and immunology, hone her critical review of the scientific literature, develop her ability to present her work in both the domestic and internationl arena, and acquire the ability to manage a laboratory. Continued access to the abundant resources and rich intellectual environment across departments and schools at Drexel University leave this candidate well-positioned to achieve this goal. This Career Development Award will serve as a driving force in Dr. Carey's success, providing the protected time and additional training required for this candidate to become an independent investigator.