Mechanisms of age-specific differences in the Type I IFN response to respiratory viral infection

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Project Summary/Abstract Respiratory viral infections contribute substantially to global infant losses and disproportionately affect preterm neonates. Of all deaths less than 12 months of age secondary to a respiratory viral infection, 55% occur in a neonate born before 30 weeks gestation. Until recently, most research about neonatal and infant primary immune response to viral infections was based on data from adult animal models generalized to the neonate. Current data suggest that a more relevant model for the human infant is the neonatal mouse because of a similar evolution of the immune system post-birth. We have established a 3-day old murine model of infant influenza virus infection, comparable to a late preterm (34-37 weeks gestation) human neonate. To determine age-specific differences in the initial innate response to influenza virus, we measured by Nanostring technology RNA transcriptional changes in 753 immune-related genes induced in neonatal and adult whole lungs 12 hours after PR8 influenza virus infection and uninfected age-matched neonates. Twelve hours after infection, the neonatal mouse had a similar transcriptional profile to an uninfected age-matched mouse, whereas the infected adult mouse upregulated hundreds of genes, especially in the type I interferon (IFN) pathway, an essential component of antiviral defense. Although type I IFNs induce key antiviral pathways, IFNs can also serve to amplify proinflammatory responses, which can increase damage in the respiratory tract in adults. However, the infant-specific type I IFN kinetic and whether type I IFNs are protective or deleterious to infants represents a significant knowledge gap. In preliminary studies, neonatal mice devoid of the type I IFN receptor (IFNαβR-/-) had a greatly improved survival rate of 80% after influenza virus infection, compared to the C57BL/6 survival rate of only 15%. This is in direct opposition to adult mice, where viral infection is more pathogenic in the absence of a type I IFN response. We hypothesize that the neonate has an aberrant type I IFN kinetic in response to influenza virus which directly leads to oxidative stress, inflammation and lung tissue damage. Since the presence of IFNαβ receptor is protective in adults, we also hypothesize that differences in neonatal IFNαβ receptor-dependent responses may involve distinct downstream pathways than the adult type I IFN response. To test this hypothesis, we propose to investigate developmental differences in the infant response to respiratory viral infection through a powerful combination of next generation sequencing, an in vivo neonatal mouse infection model and an innovative primary neonatal lung epithelial cell culture. Key in vivo transcriptome differences will be determined in neonatal and adult, naïve and influenza-infected, C57BL/6 and IFNαβR-/- FACS purified murine lung Type II epithelial cells. We will also define age-specific type I IFN kinetic differences which promote an oxidative stress response in neonatal influenza-infected lung epithelial cells which contributes to pathogenicity. Finally, we will test if an anti-oxidant (N-acetyl cysteine) is a reasonable therapeutic option to treat infant respiratory viral infection in this extremely vulnerable population.