Chlamydial infection in vitamin D receptor knockout mice is more intense and prolonged than in wild-type mice

Abstract

Vitamin D hormone (1,25-dihydroxyvitamin D) is involved in innate immunity and induces host defense peptides in epithelial cells, suggesting its involvement in mucosal defense against infections. Chlamydia trachomatis is a major cause of bacterial sexually transmitted disease worldwide. We tested the hypothesis that the vitamin D endocrine system would attenuate chlamydial infection. Vitamin D receptor knock-out mice (VDR−/−) and wild-type mice (VDR+/+) were infected with 103 inclusion forming units of Chlamydia muridarum and cervical epithelial cells (HeLa cells) were infected with C. muridarum at multiplicity of infection 5:1 in the presence and absence of 1,25-dihydroxyvitamin D3.VDR−/− mice exhibited significantly higher bacterial loading than wild-type VDR+/+ mice (P<0.01) and cleared the chlamydial infection in 39 days, compared with 18 days for VDR+/+ mice. Monocytes and neutrophils were more numerous in the uterus and oviduct of VDR−/− mice than in VDR+/+ mice (P< 0.05) at d 45 after infection. Pre-treatment of HeLa cells with 10nM or 100nM 1,25-dihydroxyvitamin D3 decreased the infectivity of C. muridarum (P< 0.001). Several differentially expressed protein spots were detected by proteomic analysis of chlamydial-infected HeLa cells pre-treated with 1,25-dihydroxyvitamin D3. Leukocyte elastase inhibitor (LEI), an anti-inflammatory protein, was up-regulated. Expression of LEI in the ovary and oviduct of infected VDR+/+ mice was greater than that of infected VDR−/− mice. We conclude that the vitamin D endocrine system reduces the risk for prolonged chlamydial infections through regulation of several proteins and that LEI is involved in its anti-inflammatory activity.

Natural Course of Chlamydia trachomatis Bacterial Load in the Time Interval between Screening and Treatment in Anogenital Samples

“…To reconstruct the natural load-curve during CT infections, mice studies may be guiding. These studies showed a steady increase in bacterial load in the early hours after infection, after which the infection reaches a stable phase and after approximately a week a steady decline in the bacterial load sets in until resolution takes place [ 10 , 11 , 25 , 26 ]. In our study, we demonstrated that the CT load is stable or decreasing in 90% of patients over time, both in urogenital and anorectal samples, consistent with the results found in animal studies.…”

Vitamin D and inflammatory diseases

“…Compared with VDR +/+ mice, VDR −/− mice exhibited significantly higher Chlamydia trachomatis loading and reduced clearance of chlamydial infection than wild-type VDR +/+ mice, suggesting a vitamin D–VDR pathway involved in respiratory mucosal defense against infections 46. VDR-knockout mice developed an unaltered Th1 response to infection due to impaired upregulation of arginase 1 expression under Leishmania infection 45.…”

Vitamin D Every Day to Keep the Infection Away?

“…Moreover, VDR KO mice displayed a relatively unchanged ability compared to WT mice to clear Mycobacterium tuberculosis , Candida albicans and Herpes simplex 1 [ 90 , 91 , 97 ]. In contrast, Chlamydia infection, which is also controlled by a Th1-mediated immune response, was more prolonged in VDR KO mice, because of a reduced expression of the anti-inflammatory leucocyte elastase inhibitor [ 98 ].…”