Schistosoma japonicum infection showed protective effects against allergic 
airway inflammation (AAI). However, controversial findings exist especially 
regarding the timing of the helminth infection and the underlying mechanisms. 
Most previous studies focused on understanding the preventive effect of S. 
japonicum infection on asthma (infection before allergen sensitization), whereas 
the protective effects of S. japonicum infection (allergen sensitization before 
infection) on asthma were rarely investigated. In this study, we investigated 
the protective effects of S. japonicum infection on AAI using a mouse model of 
OVA-induced asthma. To explore how the timing of S. japonicum infection 
influences its protective effect, the mice were percutaneously infected with 
cercaria of S. japonicum at either 1 day (infection at lung-stage during AAI) or 
14 days before ovalbumin (OVA) challenge (infection at post-lung-stage during 
AAI). We found that lung-stage S. japonicum infection significantly ameliorated 
OVA-induced AAI, whereas post-lung-stage infection did not. Mechanistically, 
lung-stage S. japonicum infection significantly upregulated the frequency of 
regulatory T cells (Treg cells), especially OVA-specific Treg cells, in lung 
tissue, which negatively correlated with the level of OVA-specific 
immunoglobulin E (IgE). Depletion of Treg cells in vivo partially counteracted 
the protective effect of lung-stage S. japonicum infection on asthma. 
Furthermore, transcriptomic analysis of lung tissue showed that lung-stage S. 
japonicum infection during AAI shaped the microenvironment to favor Treg 
induction. In conclusion, our data showed that lung-stage S. japonicum infection 
could relieve OVA-induced asthma in a mouse model. The protective effect was 
mediated by the upregulated OVA-specific Treg cells, which suppressed IgE 
production. Our results may facilitate the discovery of a novel therapy for AAI.