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Infect. Immun. doi:10.1128/IAI.01999-06
Copyright (c) 2007, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Lack of immune responses to Mycobacterium tuberculosis DosR regulon proteins following BCG vaccination

Department of Immunohematology & Blood Transfusion, Leiden University Medical Centre, The Netherlands; Department of Infectious and Tropical Diseases, London School of Hygiene & Tropical Medicine, Keppel Street, London, United Kingdom; Department of Microbiology, University of Colorado Health Sciences Center, USA; Laboratory of Mycobacterial Immunology, WIV-Pasteur Institute, B1180 Brussels, Belgium

^* To whom correspondence should be addressed. Email: t.h.m.ottenhoff{at}lumc.nl.

	Abstract

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% homology in amino acid sequence, 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 immuno-dominant TB latency antigens and found that BCG vaccination fails to induce significant responses to latency antigens. Similar results were found in BCG vaccinated BALB/c mice. In contrast, responses to latency antigens were observed in individuals with suspected exposure to TB (as indicated by positive IFN responses to TB specific antigens ESAT-6 and CFP10), 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.