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 2 a, we will examine the role of the DNA methylome in regulating CD4+ T cell responsiveness in neonatal and juvenile lung.
In aim 2 b, 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.

Public Health Relevance

Approximately 1 million children less than five years of age, die each year from pneumonia. 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 lower respiratory tract pathogens. In this proposal, we will determine how developmental differences in lung CD4+ T cell responsiveness in neonates and juveniles influence disease outcomes to pneumonia.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Study Section
Lung Injury, Repair, and Remodeling Study Section (LIRR)
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Natarajan, Aruna R
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Johns Hopkins University
Schools of Medicine
United States
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McGrath-Morrow, Sharon A; Ndeh, Roland; Helmin, Kathryn A et al. (2018) DNA methylation regulates the neonatal CD4+ T-cell response to pneumonia in mice. J Biol Chem 293:11772-11783
Vermillion, Meghan S; Ursin, Rebecca L; Kuok, Denise I T et al. (2018) Production of amphiregulin and recovery from influenza is greater in males than females. Biol Sex Differ 9:24
Morrow, Christopher B; McGrath-Morrow, Sharon A; Collaco, Joseph M (2018) Predictors of length of stay for initial hospitalization in infants with bronchopulmonary dysplasia. J Perinatol 38:1258-1265
Bernier, Meghan L; Jacob, Ariel I; Collaco, Joseph M et al. (2018) Perioperative events in children with pulmonary hypertension undergoing non-cardiac procedures. Pulm Circ 8:2045893217738143
Collaco, Joseph M; McGrath-Morrow, Sharon A (2018) Electronic Cigarettes: Exposure and Use Among Pediatric Populations. J Aerosol Med Pulm Drug Deliv 31:71-77
Laube, Beth L; Afshar-Mohajer, Nima; Koehler, Kirsten et al. (2017) Acute and chronic in vivo effects of exposure to nicotine and propylene glycol from an E-cigarette on mucociliary clearance in a murine model. Inhal Toxicol 29:197-205
Ortiz, Luis E; McGrath-Morrow, Sharon A; Sterni, Laura M et al. (2017) Sleep disordered breathing in bronchopulmonary dysplasia. Pediatr Pulmonol 52:1583-1591
McGrath-Morrow, Sharon A; Ahn, Edward S; Collaco, Joseph M (2017) Respiratory outcomes after initial hospital discharge in children with ventricular shunts and bronchopulmonary dysplasia. Pediatr Pulmonol 52:1323-1328
McGrath-Morrow, Sharon A; Ndeh, Roland; Collaco, Joseph M et al. (2017) The innate immune response to lower respiratory tract E. Coli infection and the role of the CCL2-CCR2 axis in neonatal mice. Cytokine 97:108-116
Abman, Steven H; Collaco, Joseph M; Shepherd, Edward G et al. (2017) Interdisciplinary Care of Children with Severe Bronchopulmonary Dysplasia. J Pediatr 181:12-28.e1

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