Neonatal rhinovirus induces mucous metaplasia and airways hyperresponsiveness through IL-25 and type 2 innate lymphoid cells

Abstract

Background 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. Objective We hypothesized that, in contrast to infection of mature BALB/c mice, neonatal infection with RV promotes an IL-25-driven type 2 response which causes persistent mucous metaplasia and airway hyperresponsiveness. Methods Six day-old and 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. Results Compared to mature mice, RV infection in neonatal mice increased lung IL-13 and IL-25 production whereas IFN-γ, IL-12p40 and TNF-α expression were suppressed. 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. Finally, anti-IL-25 neutralizing antibody attenuated ILC2 expansion, mucous hypersecretion and airways responsiveness. Conclusions These findings suggest that early-life viral infection could contribute to asthma development by provoking age-dependent, IL-25-driven type 2 immune responses.

IFN-γ Blocks Development of an Asthma Phenotype in Rhinovirus-Infected Baby Mice by Inhibiting Type 2 Innate Lymphoid Cells

“…In our previous report, we found that RV infection of neonatal mice induced mucous metaplasia and airways hyperresponsiveness, which was dependent on the type 2 cytokine IL-13 (12,13). In this study, we hypothesized that IFN-g counteracts the observed asthma phenotype.…”

“…Neonatal T cells and monocytes demonstrate deficient IFN-g production (14)(15)(16), as well as diminished responses to IFN-g stimulation (17,18). Accordingly, we found that IFN-g production was suppressed in RV-infected immature 6-day-old mice in comparison with 21-day-old and mature 8-week-old mice (13). Infants with reduced blood mononuclear cell production of IFN-g, the principal type 1 cytokine, have been shown to be at a greater risk of recurrent virus-induced wheezing and asthma development (19)(20)(21)(22).…”

“…We found that neonatal RV infection induced persistent mucous metaplasia and airways hyperresponsiveness, which was dependent on the type 2 cytokine IL-13 (12). More recently, we showed that RV-induced mucous metaplasia and airways hyperresponsiveness were dependent on airway epithelial cell IL-25 production and expansion of IL-13-producing ILC2s (13). Airway responses were blocked by neutralizing antibody against IL-25.…”

The impact of respiratory viruses on lung health after preterm birth

“…Furthermore, despite strong epidemiological evidence supporting the role of RV in the pathogenesis of asthma, airway reactivity and airflow limitation, the underlying mechanisms are unclear. Although damage to the developing airways and altered immune responses are thought to be the main mechanisms through which RV could induce asthma and airway hyperreactivity later in life [107,108], others have suggested that early-life infection with RV might be the first indication of the pre-existing tendency in some children to develop asthma, including among preterm infants [109,110]. The ability of RV to induce prolonged and exaggerated inflammatory responses after the initial infection has been described as a potential contributor to the development of chronic respiratory morbidity among preterm infants, with limited data demonstrating increased airway secretion of inflammatory cytokines and remodelling molecules during acute RV infection, particularly among those with BPD [108,111].…”

Andrographolide Restores Steroid Sensitivity To Block Lipopolysaccharide/IFN-γ–Induced IL-27 and Airway Hyperresponsiveness in Mice

“…R ecent studies have highlighted the role of innate immune cells including pulmonary macrophages in more severe types of asthma, which are often associated with steroidresistant airway hyperresponsiveness (AHR) (1,2). Acute exacerbations of asthma, often triggered by respiratory bacterial or viral infections, are critical clinical problems for asthma management and treatment.…”