Respiratory syncytial virus nonstructural protein 1 breaks immune tolerance in mice by downregulating Tregs through TSLP-OX40/OX40L-mTOR axis.

Respiratory syncytial virus (RSV) infection in early life is associated strongly with the subsequent development and exacerbation of asthma, however, the mechanism is still ambiguous. In this study, we identified that RSV nonstructural protein (NS) 1 plays a critical role. Plasmid-mediated overexpression of NS1 induced significant airway hyperresponsiveness, eosinophilia, and mucus hyperproduction in mice. In the pNS1 group, there were markedly elevated proportions of Th2 and Th17 cells, while Th1 and Foxp3+ regulatory T cells (Tregs) significantly declined compared with the control group. Serum concentrations of interleukin (IL)-4, IL-5, IL-6, IL-17, transforming growth factor-beta, and tumor necrosis factor-alpha increased but levels of interferon-gamma and interleukin-10 declined in pNS1 group. Besides, NS1 caused a significant rise of serum thymic stromal lymphopoietin (TSLP) and OX40L levels, and a neutralizing mAb anti-OX40L was capable of promoting RSV clearance and attenuating the airway allergic inflammation caused by pNS1. Otherwise, OX40L-blocking counteracts the inhibitory effect of pNS1 on Tregs in the spleen. RSV NS1 caused elevated levels of phospho-AKT, phospho-mTOR, and phospho-S6K1, which were partially attenuated by anti-OX40L. Moreover, a specific inhibitor of mTORC1 significantly relieved the inhibition of Foxp3 expression and Tregs differentiation. Together, the data indicate that RSV NS1 protein breaks immune tolerance and induces airway inflammation and hyperresponsiveness in mice. In this process, NS1-stimulated TSLP and OX40L play a major role by inhibiting the induction of Tregs, which is at least partially mediated by modulating AKT-mTOR signaling pathways.

miRNAs and Leukotrienes in Respiratory Syncytial Virus Infection.

MicroRNAs (miRNAs) are small, non-coding RNAs that regulate posttranscription by binding to 3'-untranslated regions of target mRNAs. Recent functional studies have elucidated mechanisms that miRNAs regulate leukotriene synthesis by perturbing arachidonic acid metabolism. Both microarrays and high-throughput sequencing revealed distinct differential expression of miRNAs in children with respiratory syncytial virus (RSV) infection compared with healthy controls. Abnormal miRNA expression may contribute to higher leukotriene levels, which is associated with airway hyperreactivity. Targeting miRNAs may benefit to restore the homeostasis of inflammatory reaction and provide new strategies to alleviate airway hyperreactivity induced by RSV. In this article, we provide an overview of the current knowledge about miRNAs modulating leukotrienes through regulation of arachidonic acid metabolism with a special focus on miRNAs aberrantly expressed in children with RSV infection.