Respiratory Syncytial Virus (RSV) is the leading cause of bronchiolitis in infants worldwide with healthcare costs estimated at $365-$585 million per year. Human epidemiological studies have identified age at initial infection as an independent risk factor for the development of childhood asthma. We have previously demonstrated in a mouse model that age of initial infection with RSV influences respiratory function in later life - infection of neonatal mice, d 7d of age, primes for a Th2 immune response that contributes to the development of long-term airways dysfunction. The mechanism(s) underlying the influence of age on the immune and pulmonary responses elicited in response to RSV infection remains obscure. Our preliminary data reveal that expression of IL-4Ra is developmentally regulated such that its expression declines on lung mDCs and Th1 cells as animals age (i.e. expression is highest in the neonate). Furthermore, downregulation of IL-4Ra expression during RSV infection in the neonate 1) inhibits the initial Th2 biased immune response and 2) protects against persistent Th2 immune deviation and pulmonary pathophysiology observed with secondary RSV infection in the adult. Our data support the expression of IL-4Ra in early life as a critical and novel age-dependent mechanism of severe RSV infection. Therefore, our hypothesis is that developmentally regulated expression of IL-4Ra on neonatal myeloid dendritic cells (mDCs) is responsible for biasing immune and pulmonary responses towards asthmatic type responses in later life. Specifically, our preliminary data suggest a unique mechanism whereby elevated levels of IL-4Ra on neonatal mDCs initiates a Th2-polarized immune response to RSV and signaling through IL-4Ra on neonatal Th1 cells results in their ablation. We will explore the validity of this hypothesis in the following specific aims:
Aim 1 will determine if age-related expression of IL-4Ra on mDCs is responsible for altered mDC function in neonatal RSV infection resulting in an asthma-promoting DC. We will leverage conditional cell ablation and adoptive transfer strategies to determine the functional role of IL-4Ra on neonatal mDCs.
Aim 2 will explore our prediction that elevated levels of IL-4Ra on neonatal Th1 cells are responsible for their specific ablation during neonatal RSV infection and for the persistence of the asthma phenotype following neonatal RSV infection.
Aim 3 will demonstrate that exacerbation of allergic asthma in adult mice is due to an altered Th2- inducing mDC formed during neonatal RSV infection. The concepts presented here are novel;and the data derived from these studies are expected to have a positive paradigm-shifting impact in understanding RSV- mediated asthma.

Public Health Relevance

RSV causes significant morbidity and mortality in infants with a global disease burden of 64 million cases and 160,000 deaths annually. Our hypothesis is that a novel age-related mechanism mediated by elevated levels of IL-4Ra in early life, exists and programs for severe RSV, asthma, and susceptibility to asthma following neonatal RSV infection. If our hypothesis is correct, the concepts established here will not only have important implications for understanding mechanisms of RSV-mediated airway disease but also for understanding neonatal immunity and mechanisms of immunomodulation relevant to the development of safer and more effective pediatric vaccines.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
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Lung Cellular, Molecular, and Immunobiology Study Section (LCMI)
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Dong, Gang
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University of Tennessee Health Science Center
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United States
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Schwingshackl, Andreas; Kimura, Dai; Rovnaghi, Cynthia R et al. (2016) Regulation of inflammatory biomarkers by intravenous methylprednisolone in pediatric ARDS patients: Results from a double-blind, placebo-controlled randomized pilot trial. Cytokine 77:63-71
Stephenson, Erin J; Ragauskas, Alyse; Jaligama, Sridhar et al. (2016) Exposure to environmentally persistent free radicals during gestation lowers energy expenditure and impairs skeletal muscle mitochondrial function in adult mice. Am J Physiol Endocrinol Metab 310:E1003-15
You, Dahui; Saravia, Jordy; Siefker, David et al. (2016) Crawling with Virus: Translational Insights from a Neonatal Mouse Model on the Pathogenesis of Respiratory Syncytial Virus in Infants. J Virol 90:2-4
Nau Jr, Felix; Miller, Justin; Saravia, Jordy et al. (2015) Serotonin 5-HTâ‚‚ receptor activation prevents allergic asthma in a mouse model. Am J Physiol Lung Cell Mol Physiol 308:L191-8
Hrincius, Eike R; Liedmann, Swantje; Finkelstein, David et al. (2015) Acute Lung Injury Results from Innate Sensing of Viruses by an ER Stress Pathway. Cell Rep 11:1591-603
Saravia, Jordy; You, Dahui; Shrestha, Bishwas et al. (2015) Respiratory Syncytial Virus Disease Is Mediated by Age-Variable IL-33. PLoS Pathog 11:e1005217
Huang, Huaqiong; Saravia, Jordy; You, Dahui et al. (2015) Impaired gamma delta T cell-derived IL-17A and inflammasome activation during early respiratory syncytial virus infection in infants. Immunol Cell Biol 93:126-35
Jaligama, Sridhar; Chen, Zaili; Saravia, Jordy et al. (2015) Exposure to Deepwater Horizon Crude Oil Burnoff Particulate Matter Induces Pulmonary Inflammation and Alters Adaptive Immune Response. Environ Sci Technol 49:8769-76
You, Dahui; Siefker, David T; Shrestha, Bishwas et al. (2015) Building a better neonatal mouse model to understand infant respiratory syncytial virus disease. Respir Res 16:91
Lomnicki, Slawo; Gullett, Brian; Stöger, Tobias et al. (2014) Combustion By-Products and their Health Effects--combustion engineering and global health in the 21st century: issues and challenges. Int J Toxicol 33:3-13

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