Potential Role of Early-life Rhinovirus Infection in the Development of Asthma.

Abstract

Early-life human rhinovirus (RV) infection has been linked to asthma development in high risk infants and children. Nevertheless, the role of RV infection in the initiation of asthma remains unclear. Because the airway epithelium is the primary target of respiratory viral infection, thymic stromal lymphopoietin (TSLP) and IL-25 and their downstream cellular targets are uniquely positioned to play a role in viral-induced chronic airways disease. We hypothesized that neonatal RV infection induces TSLP and IL-25, enhancing type 2 cytokine production from innate immune cells, thereby leading to mucous metaplasia and airways hyperresponsiveness. To resolve this issue, six day-old BALB/c mice and TSLP receptor (TSLPR) KO mice as well as eight week-old BALB/c mice were inoculated with sham HeLa cell lysate or RV. Airway responses from 1 to 28 days after infection were assessed by qPCR, ELISA, histology, immunofluorescence microscopy, flow cytometry and methacholine responsiveness. Selected mice were treated with a neutralizing antibody to IL-25. Compared to mature mice, RV infection in neonatal mice increased lung IL-13, IL-25 and TSLP production whereas IFN-gamma, IL-12p40 and TNF-alpha expression were suppressed. Induction of IL-25 and TSLP was regulated in an age-dependent manner. In addition, the population of IL-13-secreting type 2 innate lymphoid cells (ILC2s) was expanded with RV infection in neonatal but not in mature mice. ILC2 cells were the major cell type secreting IL-13 in neonates. Compared to control mice, TSLPR KO neonatal mice, or neonates treated with anti-IL-25 neutralizing antibody showed attenuated ILC2 expansion, mucous hypersecretion and airways responsiveness. When combined with IL-25 and IL-33, TSLP had a direct synergistic effect on ILC2 maturation and function. We conclude that TSLP and IL-25 is required for persistent mucus metaplasia and airway hyperresponsiveness as well as ILC2 expansion in RV-infected neonatal mice. These findings may suggest, with an appropriate genetic background, early-life RV infection may modulate and induce type 2 immune response, thereby leading to the development of persistent mucus metaplasia and airway hyperresponsiveness.