Research ArticleInfectious diseases

PTH/PTHrP and Vitamin D Control Antimicrobial Peptide Expression and Susceptibility to Bacterial Skin Infection

Science Translational Medicine  23 May 2012:
Vol. 4, Issue 135, pp. 135ra66
DOI: 10.1126/scitranslmed.3003759

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A Sunny Solution to Infectious Disease

A role for vitamin D in immune defense has been hypothesized on the basis of observations made over several decades that increased vitamin D intake, often through increased sunlight exposure, provides a therapeutic effect in fighting infectious diseases. However, a critical role for vitamin D status in immune function has not been established by controlled clinical trials. The current study by Muehleisen et al. sought to determine whether parathyroid hormone (PTH), or PTH-related peptide (PTHrP), might also act together with vitamin D in immune defense against bacterial skin infections and thus confound interpretations based solely on vitamin D status. The authors found that human skin keratinocytes showed increased expression of PTHrP in response to bacterial products. PTH or PTHrP was then observed to induce expression of cathelicidin antimicrobial peptide by keratinocytes in culture. When PTH was administered to mice, it enhanced their resistance to skin infection by group A Streptococcus. If vitamin D was absent from the diet of normal mice, they responded with an increase in PTH production and an increase in antimicrobial peptide expression. However, mice lacking the capacity to convert vitamin D to 1,25-vitamin D failed to induce cathelicidin in response to restriction of dietary vitamin D and became much more susceptible to invasive bacterial infection. Because 1,25-dihydroxyvitamin D was found necessary for keratinocytes to express the PTH/PTHrP receptor, this increase in susceptibility to infection may reflect the inability of PTH or PTHrP to induce cathelicidin in a setting of low vitamin D. These findings show that PTH/PTHrP is immunologically active, can boost innate immunity, and may compensate for low vitamin D status. Understanding this system provides a new target for studying the immunological functions of vitamin D.