Immunomodulation with IL-4Rα Antisense Oligonucleotide Prevents Respiratory Syncytial Virus-Mediated Pulmonary Disease

Abstract

Respiratory syncytial virus (RSV) causes significant morbidity and mortality in infants worldwide. Severe RSV infections in infants cause bronchiolitis, wheeze, and/or cough and significantly increase the risk for developing asthma. RSV pathogenesis is thought to be due to a Th2-type immune response initiated in response to RSV infection, specifically in the infant. Using a neonatal mouse system as an appropriate model for human infants, we sought to determine whether local inhibition of IL-4Rα expression during primary RSV infection in the neonate would prevent Th2-skewed responses to secondary RSV infection and improve long-term pulmonary function. To reduce IL-4Rα expression, antisense oligonucleotides (ASOs) specific for IL-4Rα were administered intranasally to neonatal mice at the time of primary infection. Mice were initially infected with RSV at 1 wk of age and were reinfected at 6 wk of age. Administration of IL-4Rα ASOs during primary RSV infection in neonatal mice abolished the pulmonary dysfunction normally observed following reinfection in the adult. This ablation of pulmonary dysfunction correlated with a persistent rebalancing of the Th cell compartment with decreased Th2 responses (i.e., reduced goblet cell hyperplasia, Th2 cells, and cytokine secretion) and increased Th1 responses (i.e., elevated Th1 cell numbers and type I Abs and cytokines). Our data support our hypothesis that a reduction in the Th2 immune response during primary infection in neonates prevents Th2-mediated pulmonary pathology initially and upon reinfection and further suggest that vaccine strategies incorporating IL-4Rα ASOs may be of significant benefit to infants.

Limited Type I Interferons and Plasmacytoid Dendritic Cells during Neonatal Respiratory Syncytial Virus Infection Permit Immunopathogenesis upon Reinfection

“…In fact, these results were strikingly similar to those that we previously obtained with antisense oligonucleotides to IL-4R␣: the moderate downregulation of IL-4R␣ during neonatal RSV infection completely abolished reinfection-associated airway hyperactivity and significantly decreased Th2-biased responses (6). We believe this phenomenon to be due to fine-tuning of IL-4R␣ signaling, which results in a rebalancing of the immune response so that Th2 cells no longer skew the immune response.…”

“…Although it is difficult to dissociate the antiviral effects of IFN-␣, our previous study clearly demonstrated that enhanced IL-4R␣ expression on neonatal Th cells compared to that on adult Th cells plays a significant role in the development of the Th2-biased immunopathologies following RSV reinfection (4). Furthermore, the reduction of IL-4R␣ on Th2 cells during primary infection prevents Th2 bias, airway hyperreactivity, mucus hyperproduction, and inflammation upon reinfection without affecting the viral load (6). In line with this observation, the data presented here demonstrate that IFN-␣ treatment prior to RSV infection reduces the expression of IL-4R␣ on Th2 cells (Fig.…”

“…Our and other laboratories have therefore developed a neonatal mouse model that better mimics RSV disease in infants (4)(5)(6)(7)(8)(9). In this model, neonatal mice (Ͻ7 days old) are infected with RSV and various immunological parameters are measured.…”

“…In this model, neonatal mice (Ͻ7 days old) are infected with RSV and various immunological parameters are measured. Notably, RSV-infected neonates mount limited Th1 (CD3 (4,6,8,9) and multifunctional Th (CD3 ϩ , CD4 ϩ , IFN-␥ ϩ , IL-4 ϩ ) cells (4), while the number of Th1 cells upon reinfection is equivalent to that in mice initially infected as adults. This biased Th2 response observed upon reinfection is associated with enhanced airway hyperreactivity (AHR), airway and lung eosinophilia, and mucus hyperproduction (4,6,8,9), all of which are consistent with the observations for infants from the 1960s clinical trials who died from community-acquired RSV infection (3).…”

TLR4 genotype and environmental LPS mediate RSV bronchiolitis through Th2 polarization

“…It is, however, clear that these forms of sampling represent the mixture of conventional Th2 contributions (in ours and other studies, ref. 44) with those of a number of other cell types. With respect to CD4 + T cells, for instance, a major source of IL-9 would be the Th9 cell population (45).…”