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Research Article

Vitamin D accelerates resolution of inflammatory responses during tuberculosis treatment

Anna K. Coussens, Robert J. Wilkinson, Yasmeen Hanifa, Vladyslav Nikolayevskyy, Paul T. Elkington, Kamrul Islam, Peter M. Timms, Timothy R. Venton, Graham H. Bothamley, Geoffrey E. Packe, Mathina Darmalingam, Robert N. Davidson, Heather J. Milburn, Lucy V. Baker, Richard D. Barker, Charles A. Mein, Leena Bhaw-Rosun, Rosamond Nuamah, Douglas B. Young, Francis A. Drobniewski, Christopher J. Griffiths, and Adrian R. Martineau
  1. aDivision of Mycobacterial Research, Medical Research Council National Institute for Medical Research, London NW7 1AA, United Kingdom;
  2. bDivision of Medicine, Imperial College London, London W2 1PG, United Kingdom;
  3. cBlizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AB, United Kingdom;
  4. dHealth Protection Agency National Mycobacterium Reference Laboratory, Barts and The London School of Medicine and Dentistry, London E1 2AT, United Kingdom;
  5. eDepartment of Infectious Diseases and Immunity, Imperial College London, London W12 0NN, United Kingdom;
  6. fHomerton University Hospital, London E9 6SR, United Kingdom;
  7. gNewham Chest Clinic, Forest Gate, London E7 8QP, United Kingdom;
  8. hDepartment of Respiratory Medicine, Whipps Cross University Hospital, London E11 1NR, United Kingdom;
  9. iTuberculosis Clinic, Northwick Park Hospital, Harrow HA1 3UJ, United Kingdom;
  10. jDepartment of Respiratory Medicine, Guy’s and St Thomas’ Hospitals, London SE1 9RT, United Kingdom;
  11. kDepartment of Respiratory Medicine, Lewisham Hospital, London SE13 6LH, United Kingdom;
  12. lDepartment of Respiratory Medicine, Kings College Hospital, London SE5 9RS, United Kingdom; and
  13. mGenome Centre, Barts and The London School of Medicine, Queen Mary University of London, London EC1M 6BQ, United Kingdom

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PNAS September 18, 2012 109 (38) 15449-15454; https://doi.org/10.1073/pnas.1200072109
Anna K. Coussens
aDivision of Mycobacterial Research, Medical Research Council National Institute for Medical Research, London NW7 1AA, United Kingdom;
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Robert J. Wilkinson
aDivision of Mycobacterial Research, Medical Research Council National Institute for Medical Research, London NW7 1AA, United Kingdom;
bDivision of Medicine, Imperial College London, London W2 1PG, United Kingdom;
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Yasmeen Hanifa
cBlizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AB, United Kingdom;
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Vladyslav Nikolayevskyy
dHealth Protection Agency National Mycobacterium Reference Laboratory, Barts and The London School of Medicine and Dentistry, London E1 2AT, United Kingdom;
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Paul T. Elkington
eDepartment of Infectious Diseases and Immunity, Imperial College London, London W12 0NN, United Kingdom;
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Kamrul Islam
cBlizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AB, United Kingdom;
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Peter M. Timms
fHomerton University Hospital, London E9 6SR, United Kingdom;
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Timothy R. Venton
fHomerton University Hospital, London E9 6SR, United Kingdom;
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Graham H. Bothamley
fHomerton University Hospital, London E9 6SR, United Kingdom;
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Geoffrey E. Packe
gNewham Chest Clinic, Forest Gate, London E7 8QP, United Kingdom;
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Mathina Darmalingam
hDepartment of Respiratory Medicine, Whipps Cross University Hospital, London E11 1NR, United Kingdom;
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Robert N. Davidson
iTuberculosis Clinic, Northwick Park Hospital, Harrow HA1 3UJ, United Kingdom;
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Heather J. Milburn
jDepartment of Respiratory Medicine, Guy’s and St Thomas’ Hospitals, London SE1 9RT, United Kingdom;
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Lucy V. Baker
kDepartment of Respiratory Medicine, Lewisham Hospital, London SE13 6LH, United Kingdom;
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Richard D. Barker
lDepartment of Respiratory Medicine, Kings College Hospital, London SE5 9RS, United Kingdom; and
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Charles A. Mein
mGenome Centre, Barts and The London School of Medicine, Queen Mary University of London, London EC1M 6BQ, United Kingdom
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Leena Bhaw-Rosun
mGenome Centre, Barts and The London School of Medicine, Queen Mary University of London, London EC1M 6BQ, United Kingdom
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Rosamond Nuamah
mGenome Centre, Barts and The London School of Medicine, Queen Mary University of London, London EC1M 6BQ, United Kingdom
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Douglas B. Young
aDivision of Mycobacterial Research, Medical Research Council National Institute for Medical Research, London NW7 1AA, United Kingdom;
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Francis A. Drobniewski
dHealth Protection Agency National Mycobacterium Reference Laboratory, Barts and The London School of Medicine and Dentistry, London E1 2AT, United Kingdom;
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Christopher J. Griffiths
cBlizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AB, United Kingdom;
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Adrian R. Martineau
cBlizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AB, United Kingdom;
aDivision of Mycobacterial Research, Medical Research Council National Institute for Medical Research, London NW7 1AA, United Kingdom;
bDivision of Medicine, Imperial College London, London W2 1PG, United Kingdom;
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  • For correspondence: a.martineau@qmul.ac.uk
  1. Edited* by Barry R. Bloom, Harvard School of Public Health, Boston, MA, and approved July 25, 2012 (received for review January 18, 2012)

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Abstract

Calcidiol, the major circulating metabolite of vitamin D, supports induction of pleiotropic antimicrobial responses in vitro. Vitamin D supplementation elevates circulating calcidiol concentrations, and thus has a potential role in the prevention and treatment of infection. The immunomodulatory effects of administering vitamin D to humans with an infectious disease have not previously been reported. To characterize these effects, we conducted a detailed longitudinal study of circulating and antigen-stimulated immune responses in ninety-five patients receiving antimicrobial therapy for pulmonary tuberculosis who were randomized to receive adjunctive high-dose vitamin D or placebo in a clinical trial, and who fulfilled criteria for per-protocol analysis. Vitamin D supplementation accelerated sputum smear conversion and enhanced treatment-induced resolution of lymphopaenia, monocytosis, hypercytokinaemia, and hyperchemokinaemia. Administration of vitamin D also suppressed antigen-stimulated proinflammatory cytokine responses, but attenuated the suppressive effect of antimicrobial therapy on antigen-stimulated secretion of IL-4, CC chemokine ligand 5, and IFN-α. We demonstrate a previously unappreciated role for vitamin D supplementation in accelerating resolution of inflammatory responses during tuberculosis treatment. Our findings suggest a potential role for adjunctive vitamin D supplementation in the treatment of pulmonary infections to accelerate resolution of inflammatory responses associated with increased risk of mortality.

  • adjunctive therapy
  • immunomodulation
  • antimicrobial peptides
  • matrix metalloproteinases
  • steroid hormones

Footnotes

  • ↵1To whom correspondence should be addressed. E-mail: a.martineau{at}qmul.ac.uk.
  • Author contributions: C.J.G. and A.R.M. designed research; A.K.C., R.J.W., Y.H., V.N., P.T.E., K.I., P.M.T., T.R.V., G.H.B., G.E.P., M.D., R.N.D., H.J.M., L.V.B., R.D.B., C.A.M., L.B.-R., R.N., D.B.Y., F.A.D., C.J.G., and A.R.M. performed research; A.K.C. and A.R.M. analyzed data; and A.K.C. and A.R.M. wrote the paper.

  • Conflict of interest statement: Merck Serono donated €7,000 to Queen Mary University of London in 2010 to support an academic meeting entitled “Vitamin D: Mechanisms of Action in Health and Disease”; this meeting was convened by C.J.G. and A.R.M.

  • ↵*This Direct Submission article had a prearranged editor.

  • This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1200072109/-/DCSupplemental.

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Vitamin D and tuberculosis
Anna K. Coussens, Robert J. Wilkinson, Yasmeen Hanifa, Vladyslav Nikolayevskyy, Paul T. Elkington, Kamrul Islam, Peter M. Timms, Timothy R. Venton, Graham H. Bothamley, Geoffrey E. Packe, Mathina Darmalingam, Robert N. Davidson, Heather J. Milburn, Lucy V. Baker, Richard D. Barker, Charles A. Mein, Leena Bhaw-Rosun, Rosamond Nuamah, Douglas B. Young, Francis A. Drobniewski, Christopher J. Griffiths, Adrian R. Martineau
Proceedings of the National Academy of Sciences Sep 2012, 109 (38) 15449-15454; DOI: 10.1073/pnas.1200072109

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Vitamin D and tuberculosis
Anna K. Coussens, Robert J. Wilkinson, Yasmeen Hanifa, Vladyslav Nikolayevskyy, Paul T. Elkington, Kamrul Islam, Peter M. Timms, Timothy R. Venton, Graham H. Bothamley, Geoffrey E. Packe, Mathina Darmalingam, Robert N. Davidson, Heather J. Milburn, Lucy V. Baker, Richard D. Barker, Charles A. Mein, Leena Bhaw-Rosun, Rosamond Nuamah, Douglas B. Young, Francis A. Drobniewski, Christopher J. Griffiths, Adrian R. Martineau
Proceedings of the National Academy of Sciences Sep 2012, 109 (38) 15449-15454; DOI: 10.1073/pnas.1200072109
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