Role of Dendritic Cells in Pathology of Respiratory Syncytial Virus Infection in Neonates
type: CreativeWork
description: Respiratory syncytial virus (RSV) is one of the leading causes of bronchiolitis in children. We have shown that neonatal mice respond to primary RSV infection with T helper type 2 (Th2) biased immune responses, which are enhanced following reinfection. Dendritic cells (DCs) including myeloid DCs (mDCs) and plasmacytoid DCs (pDCs) play important roles in driving host responses to RSV infection. mDCs present antigens to help Th cells differentiate, and pDCs protect against viral infection through type I interferons (IFNs). Despite data demonstrating importance of mDCs and pDCs in protection against RSV, it has not been studied in an age appropriate model. Using a neonatal mouse model, we have shown that downregulation of IL-4 receptor alpha (IL-4Rα) on pulmonary myeloid dendritic cells (mDCs) via antisense oligonucleotides protected against RSV induced Th2 immunopathology. Thus, we examined the role of IL-4Rα on mDCs in RSV infection. Here, we discovered that IL-4Rα is developmentally regulated such that neonates have higher levels of IL-4Rα on mDCs. To determine if this elevated expression of IL-4Rα on mDCs was responsible for RSV pathogenesis in neonatal mice, we specifically deleted it from neonatal mDCs (or overexpressed it on adult mDCs) and studied RSV pathogenesis using our neonatal mouse model of RSV infection. Deletion of IL-4Rα from mDCs in our neonatal RSV infection model resulted in reduced disease as evidenced by reduction in Th2 biased inflammation and mucus cell hyperplasia and production. This was accompanied by improved lung function and enhanced mDC maturation status after infection. Furthermore, overexpression of IL-4Rα on adult mDCs was able to induce RSV disease similar to that observed in our neonatal model of RSV infection (i.e., Th2 biased responses including mucus hyperproduction). In vitro CD4+ T cell differentiation assays using mDCs from neonatal littermate control or IL-4Rα-/- mice were also performed to determine the specificity of the in…
abstract: Respiratory syncytial virus (RSV) is one of the leading causes of bronchiolitis in children. We have shown that neonatal mice respond to primary RSV infection with T helper type 2 (Th2) biased immune responses, which are enhanced following reinfection. Dendritic cells (DCs) including myeloid DCs (mDCs) and plasmacytoid DCs (pDCs) play important roles in driving host responses to RSV infection. mDCs present antigens to help Th cells differentiate, and pDCs protect against viral infection through type I interferons (IFNs). Despite data demonstrating importance of mDCs and pDCs in protection against RSV, it has not been studied in an age appropriate model. Using a neonatal mouse model, we have shown that downregulation of IL-4 receptor alpha (IL-4Rα) on pulmonary myeloid dendritic cells (mDCs) via antisense oligonucleotides protected against RSV induced Th2 immunopathology. Thus, we examined the role of IL-4Rα on mDCs in RSV infection. Here, we discovered that IL-4Rα is developmentally regulated such that neonates have higher levels of IL-4Rα on mDCs. To determine if this elevated expression of IL-4Rα on mDCs was responsible for RSV pathogenesis in neonatal mice, we specifically deleted it from neonatal mDCs (or overexpressed it on adult mDCs) and studied RSV pathogenesis using our neonatal mouse model of RSV infection. Deletion of IL-4Rα from mDCs in our neonatal RSV infection model resulted in reduced disease as evidenced by reduction in Th2 biased inflammation and mucus cell hyperplasia and production. This was accompanied by improved lung function and enhanced mDC maturation status after infection. Furthermore, overexpression of IL-4Rα on adult mDCs was able to induce RSV disease similar to that observed in our neonatal model of RSV infection (i.e., Th2 biased responses including mucus hyperproduction). In vitro CD4+ T cell differentiation assays using mDCs from neonatal littermate control or IL-4Rα-/- mice were also performed to determine the specificity of the in…
author: Shrestha, Bishwas
keywords: Dendritic cells, Neonates, RSV, Th2, Biological Phenomena, Cell Phenomena, and Immunity, Diseases, Medical Biochemistry, Medical Cell Biology, Medical Molecular Biology, Medical Sciences, Medicine and Health Sciences, Virus Diseases
date published: 2017-05-01T07:00:00Z
date modified: 2026-07-24T05:00:33Z
provider: University of Tennessee Health Science Center
publisher: Networked Digital Library of Theses and Dissertations
type: WebPage
source organization: University of Tennessee Health Science Center