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 ) Fok I 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 Fok I polymorphism predisposes to severe RSV bronchiolitis. We investigated how the VDR Fok I polymorphism regulates the epithelial response to RSV infection. To this end, we over‐expressed the normal and Fok I VDR variants in A549 airway epithelial cells. Vitamin D restrained the expression of both NF κ B‐ and STAT1‐induced antiviral genes. However, while NF κ B 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 Fok I epithelial cells. The poor capacity of vitamin D to regulate IRF1 in Fok I VDR‐expressing cells was recapitulated using blood samples from normal and FokI VDR‐genotyped healthy donors. Hence, we provide mechanistic insight that the Fok I 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. Copyright © 2013 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.