Resolution of Diffuse Inflammatory Lung Injury in Neonatal Mice

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ABSTRACT Pneumonia is a leading cause of death in children less than 5 years of age and it is the most common cause of mortality in children living in developing countries. Each year there are an estimated 150 million cases of childhood pneumonia worldwide resulting in approximately one million children dying each year. Although vaccines and antibiotics have dramatically improved outcomes in older children with lower respiratory tract infections, infants and young children disproportionately suffer from the highest morbidity and mortality from pneumonia. In addition, the long-term effects of childhood pneumonia can lead to impaired lung function in adult life and increase the risk of developing chronic obstructive lung disease. With these highly significant medical and public health outcomes in mind, there is a need for a more in- depth understanding of the neonate/infant lung immune response to pneumonia. Questions that require further investigation include; identifying mechanisms that regulate age and sex differences in immune responsiveness to lower respiratory tract infections (LRTI), how these variables influence short and long-term outcomes to LRTIs and whether regulators of immune responsiveness in the lung can be altered to attenuate disease severity in the neonate and young child. Thus identifying approaches that can boost the neonatal immune system during lower respiratory tract illnesses could potentially improve outcomes. Our preliminary studies indicate that lung CD4+ T cells in neonates are hypo-responsive to LRT E. coli. Since CD4+ T cells are critically important for host responsiveness to LRTI as evident by genetic and acquired deficiencies, we will focus on regulatory mechanisms that underlie CD4+ T cell responsiveness in neonatal lung. In this proposal, we will build on studies supported by our previous proposal, to examine age-related differences in lung CD4+ T cell responsiveness to E. coli pneumonia. We will examine the role of the DNA methylome in regulating neonatal lung CD4+ T cell responses to pneumonia and determine if DNA methyltransferase inhibitors can disrupt the normal neonatal CD4+ T cell response to LRTI. Finally, we will examine if sex-specific differences in respiratory outcomes to H1N1 in adults are determined by differential methylation of promoter sites in CD4+ T cell genes that are critical to the host response to influenza. In aim 1, we will focus on CD4+ T cell-derived IL-22, IFN, and AREG to determine their role in the lung’s host response to LRTIs in the neonate and juvenile. In aim 2a, we will examine the role of the DNA methylome in regulating CD4+ T cell responsiveness in neonatal and juvenile lung. In aim 2b, we will determine if exposure to LRT E. coli during childhood can alter lung CD4+ T cell responsiveness in a sex-specific manner in adults with influenza, through changes in DNA methylation promoter sites. Together, these studies will provide mechanistic insights into age-related differences in LRTI outcomes and the influence of childhood bacterial exposures on the immune response to lung infections in adults.