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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
1R01AI090059-01A1
Application #
8184844
Study Section
Lung Cellular, Molecular, and Immunobiology Study Section (LCMI)
Program Officer
Dong, Gang
Project Start
2011-08-01
Project End
2015-07-31
Budget Start
2011-08-01
Budget End
2012-07-31
Support Year
1
Fiscal Year
2011
Total Cost
$352,519
Indirect Cost
Name
Louisiana State Univ Hsc New Orleans
Department
Pharmacology
Type
Schools of Medicine
DUNS #
782627814
City
New Orleans
State
LA
Country
United States
Zip Code
70112
Shrestha, Bishwas; You, Dahui; Saravia, Jordy et al. (2017) IL-4R? on dendritic cells in neonates and Th2 immunopathology in respiratory syncytial virus infection. J Leukoc Biol 102:153-161
Oyana, Tonny J; Podila, Pradeep; Wesley, Jagila Minso et al. (2017) Spatiotemporal patterns of childhood asthma hospitalization and utilization in Memphis Metropolitan Area from 2005 to 2015. J Asthma 54:842-855
Fitzpatrick, Elizabeth A; You, Dahui; Shrestha, Bishwas et al. (2017) A Neonatal Murine Model of MRSA Pneumonia. PLoS One 12:e0169273
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
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
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Nau Jr, Felix; Miller, Justin; Saravia, Jordy et al. (2015) Serotonin 5-HT? receptor activation prevents allergic asthma in a mouse model. Am J Physiol Lung Cell Mol Physiol 308:L191-8
Saravia, Jordy; You, Dahui; Shrestha, Bishwas et al. (2015) Respiratory Syncytial Virus Disease Is Mediated by Age-Variable IL-33. PLoS Pathog 11:e1005217
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

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