Defective control of vitamin D receptor‐mediated epithelial STAT1 signalling predisposes to severe respiratory syncytial virus bronchiolitis. Issue 1 (January 2014)

• Record Type: Journal Article
• Authors: Stoppelenburg, Arie Jan; von Hegedus, Johannes Hendrick; Huis in't Veld, Ron; Bont, Louis; Boes, Marianne
• Is Part Of: Journal of pathology. Volume 232:Issue 1(2014)
• Page Start: 57
• Page End: 64
• Publication Date: 2014-01
• Subjects: Pathology -- Periodicals; 616.07
• DOI: 10.1002/path.4267
• Languages: English
• ISSNs: 0022-3417

Abstract

<abstract abstract-type="main" id="path4267-abs-0001"> <title>Abstract</title> <p id="path4267-para-0001"> <bold>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) <italic>Fok</italic>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 <italic>Fok</italic>I polymorphism predisposes to severe RSV bronchiolitis. We investigated how the VDR <italic>Fok</italic>I polymorphism regulates the epithelial response to RSV infection. To this end, we over‐expressed the normal and <italic>Fok</italic>I VDR variants in A549 airway epithelial cells. Vitamin D restrained the expression of both NF<italic>κ</italic>B‐ and STAT1‐induced antiviral genes. However, while NF<italic>κ</italic>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 <italic>Fok</italic>I epithelial cells. The poor capacity of vitamin D to regulate IRF1 in <italic>Fok</italic>I VDR‐expressing cells was recapitulated using blood samples from normal and <italic>FokI</italic> VDR‐genotyped healthy donors. Hence, we provide mechanistic insight that the <italic>Fok</italic>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.</bold> </p> </abstract>