Defective control of vitamin D receptor-mediated epithelial STAT1 signalling predisposes to severe respiratory syncytial virus bronchiolitis

Respiratory syncytial virus (RSV) infection causes bronchiolitis in infants with seasonal frequency, for which vitamin D deficiency and a well-described polymorphism in the vitamin D receptor (VDR) FokI are important risk factors. Recent studies suggest that vitamin D regulates immune pathways in airway epithelial cells during RSV infection. It is not understood why the VDR FokI polymorphism predisposes to severe RSV bronchiolitis. We investigated how the VDR FokI polymorphism regulates the epithelial response to RSV infection. To this end, we over-expressed the normal and FokI VDR variants in A549 airway epithelial cells. Vitamin D restrained the expression of both NFκB- and STAT1-induced antiviral genes. However, while NFκB control by vitamin D remained intact, both RSV-induced phosphorylation of STAT1 and expression of its downstream targets, IRF1 and IRF7, escaped vitamin D control in FokI epithelial cells. The poor capacity of vitamin D to regulate IRF1 in FokI VDR-expressing cells was recapitulated using blood samples from normal and FokI VDR-genotyped healthy donors. Hence, we provide mechanistic insight that the FokI VDR polymorphism renders STAT1-mediated antiviral immune reactions to RSV infection non-responsive to vitamin D control, resulting in enhanced immunopathology and exacerbated RSV bronchiolitis.