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Lack of Immune Responses to Mycobacterium tuberculosis DosR Regulon Proteins following Mycobacterium bovis BCG Vaccination

May Young Lin,¹ Annemieke Geluk,¹ Steven G. Smith,² Amanda L. Stewart,³ Annemieke H. Friggen,¹ Kees L. M. C. Franken,¹ Marleen J. C. Verduyn,¹ Krista E. van Meijgaarden,¹ Martin I. Voskuil,³ Hazel M. Dockrell,² Kris Huygen,⁴ Tom H. M. Ottenhoff,^1* and Michèl R. Klein^1,

Department of Immunohematology and Blood Transfusion and Department of Infectious Diseases, Leiden University Medical Center, Leiden, The Netherlands,¹ Department of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, Keppel Street, London, United Kingdom,² Department of Microbiology, University of Colorado Health Sciences Center, Denver, Colorado,³ Laboratory of Mycobacterial Immunology, WIV-Pasteur Institute, B1180 Brussels, Belgium⁴

Received 21 December 2006/ Returned for modification 12 February 2007/ Accepted 2 May 2007

Mycobacterium bovis BCG is widely used as a vaccine against tuberculosis (TB), despite its variable protective efficacy. Relatively little is known about the immune response profiles following BCG vaccination in relation to protection against TB. Here we tested whether BCG vaccination results in immune responses to DosR (Rv3133c) regulon-encoded proteins. These so-called TB latency antigens are targeted by the immune system during persistent Mycobacterium tuberculosis infection and have been associated with immunity against latent M. tuberculosis infection. In silico analysis of the DosR regulon in BCG and M. tuberculosis showed at least 97% amino acid sequence homology, with 41 out of 48 genes being identical. Transcriptional profiling of 14 different BCG strains, under hypoxia and nitric oxide exposure in vitro, revealed a functional DosR regulon similar to that observed in M. tuberculosis. Next, we assessed human immune responses to a series of immunodominant TB latency antigens and found that BCG vaccination fails to induce significant responses to latency antigens. Similar results were obtained with BCG-vaccinated BALB/c mice. In contrast, responses to latency antigens were observed in individuals with suspected exposure to TB (as indicated by positive gamma interferon responses to TB-specific antigens ESAT-6 and CFP-10) and in mice vaccinated with plasmid DNA encoding selected latency antigens. Since immune responses to TB latency antigens have been associated with control of latent M. tuberculosis infection, our findings support the development of vaccination strategies incorporating DosR regulon antigens to complement and improve the current BCG vaccine.

Published ahead of print on 14 May 2007.

Editor: J. L. Flynn

Present address: National Institute of Public Health and the Environment, 3721 MA, Bilthoven, The Netherlands.