title: Human cytomegalovirus infection downregulates vitamin-D receptor in mammalian cells.
abstract: Vitamin D (VD) is essential for the human body and involved in a wide variety of critical physiological processes including bone, muscle, and cardiovascular health, as well as innate immunity and antimicrobial responses. Here, we elucidated the significance of the VD system in cytomegalovirus (CMV) infection, which is one of the most common opportunistic infections in immunocompromised or -suppressed patients. We found that expression of vitamin D receptor (VDR) was downregulated in CMV-infected cells within 12h [hrs] post infection [p.i.] to 12% relative to VDR expression in mock-infected fibroblasts and did not recover during the CMV replication cycle of 96h. None of the biologically active metabolites of VD, cholecalciferol, calcidiol, or calcitriol, inhibit CMV replication significantly in human fibroblasts. In a feedback loop, expression of CYP24A1 dropped to 3% by 12h p.i. and expression of CYP27B1 increased gradually during the replication cycle of CMV to 970% probably as a consequence of VDR inhibition. VDR expression was not downregulated during influenza virus or adenovirus replication. The potent synthetic vitamin D analog EB-1089 was not able to inhibit CMV replication or antagonize its effect on VDR expression. Only CMV replication, and none of the other viral pathogens evaluated, inhibited the vitamin D system in vitro. In view of the pleiotropism of VDR, CMV-mediated downregulation may have far-reaching virological, immunological, and clinical implications and thus warrant further evaluations in vitro and in vivo.
authors: Department of Medicine I, Division of Infectious Diseases and Tropical Medicine, Medical University of Vienna, Vienna, Austria.
authors: Franz J J
authors: FJJ
authors: Rieder
authors: Department of Pathophysiology and Allergy Research, Medical University of Vienna, Vienna, Austria.
authors: Charlotte
authors: C
authors: Gröschel
authors: Department of Medicine I, Division of Infectious Diseases and Tropical Medicine, Medical University of Vienna, Vienna, Austria.
authors: Marie-Theres
authors: MT
authors: Kastner
authors: Children's Cancer Research Institute, Vienna, Austria.
authors: Karin
authors: K
authors: Kosulin
authors: Department of Surgery, Medical University of Vienna, Vienna, Austria.
authors: Johannes
authors: J
authors: Laengle
authors: Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria.
authors: Rene
authors: R
authors: Zadnikar
authors: Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria.
authors: Rodrig
authors: R
authors: Marculescu
authors: Department of Medicine I, Division of Infectious Diseases and Tropical Medicine, Medical University of Vienna, Vienna, Austria.
authors: Martina
authors: M
authors: Schneider
authors: Children's Cancer Research Institute, Vienna, Austria; Department of Pediatrics, Medical University of Vienna, Vienna, Austria.
authors: Thomas
authors: T
authors: Lion
authors: Department of Surgery, Medical University of Vienna, Vienna, Austria.
authors: Michael
authors: M
authors: Bergmann
authors: Department of Pathophysiology and Allergy Research, Medical University of Vienna, Vienna, Austria.
authors: Enikö
authors: E
authors: Kallay
authors: Department of Medicine I, Division of Infectious Diseases and Tropical Medicine, Medical University of Vienna, Vienna, Austria. Electronic address: christoph.steininger@meduniwien.ac.at.
authors: Christoph
authors: C
authors: Steininger
mesh_terms: D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase / Q000378:metabolism; D000072283:A549 Cells; D000256:Adenoviridae; D000818:Animals; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D003587:Cytomegalovirus; D003586:Cytomegalovirus Infections / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D005347:Fibroblasts / Q000378:metabolism / Q000821:virology; D005786:Gene Expression Regulation; D006801:Humans; D009975:Orthomyxoviridae; D018167:Receptors, Calcitriol / Q000378:metabolism*; D014709:Vero Cells; D014807:Vitamin D / Q000378:metabolism; D065668:Vitamin D3 24-Hydroxylase / Q000378:metabolism
chemical_list: D018167:Receptors, Calcitriol; C579457:VDR protein, human; D014807:Vitamin D; D065668:Vitamin D3 24-Hydroxylase; D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase
keywords: CYP24A1; CYP27B1; Calcitriol; EB-1089; Human cytomegalovirus (CMV); Vitamin D receptor