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Infection and Immunity, November 2009, p. 5071-5079, Vol. 77, No. 11
0019-9567/09/$08.00+0     doi:10.1128/IAI.00457-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Cross-Reactive Immunity to Mycobacterium tuberculosis DosR Regulon-Encoded Antigens in Individuals Infected with Environmental, Nontuberculous Mycobacteria{triangledown} ,{dagger}

May Young Lin,1 T. B. K. Reddy,2 Sandra M. Arend,1 Annemieke H. Friggen,1 Kees L. M. C. Franken,1 Krista E. van Meijgaarden,1 Marleen J. C. Verduyn,1 Gary K. Schoolnik,3 Michel R. Klein,1,{ddagger} and Tom H. M. Ottenhoff1*

Department of Infectious Diseases, Leiden University Medical Centre, Leiden, The Netherlands,1 Department of Biochemistry,2 Department of Medicine, Division of Infectious Diseases and Geographic Medicine, Stanford University School of Medicine, Palo Alto, California3

Received 23 April 2009/ Returned for modification 4 June 2009/ Accepted 28 August 2009

Mycobacterium tuberculosis DosR regulon-encoded antigens are highly immunogenic in M. tuberculosis-infected humans and are associated with latent tuberculosis infection. We have investigated the hypothesis that infection with or exposure to nontuberculous mycobacteria (NTM) can induce cross-reactive immunity to M. tuberculosis DosR regulon-encoded antigens since responsiveness has been observed in non-M. tuberculosis-exposed but purified protein derivative-responsive individuals. M. tuberculosis DosR regulon-encoded antigen-specific T-cell responses were studied in peripheral blood mononuclear cells (PBMCs) of NTM-infected/exposed individuals. BLASTP was used to determine the presence of M. tuberculosis DosR regulon-encoded protein orthologs among environmental mycobacteria and nonmycobacteria. Significant gamma interferon production was observed in PBMCs from NTM-infected/exposed individuals in response to M. tuberculosis DosR regulon-encoded antigens. DosR regulon-encoded protein orthologs were prominently present in tuberculous and environmental mycobacteria and surprisingly also in nonmycobacteria. The ubiquitous presence of the highly conserved DosR master regulator protein Rv3133c suggests that this is a general adaptive bacterial response regulator. We report a first series of M. tuberculosis antigens to which cross-reactive immunity is induced by NTM infection/exposure. The high conservation of M. tuberculosis DosR regulon-encoded antigens most likely enables them to induce cross-reactive T-cell responses.

* Corresponding author. Mailing address: Department of Infectious Diseases, Leiden University Medical Centre, C5-P, P.O. Box 9600, 2300 RC Leiden, The Netherlands. Phone: 31 71 526 2620. Fax: 31 71 526 6758. E-mail: t.h.m.ottenhoff{at}lumc.nl

{triangledown} Published ahead of print on 8 September 2009.

{dagger} Supplemental material for this article may be found at http://iai.asm.org/.

Editor: B. A. McCormick

{ddagger} Present address: National Institute for Public Health and the Environment, Centre for Infectious Disease Control Netherlands, P.O. Box 1, 3720 BA, Bilthoven, The Netherlands.

Infection and Immunity, November 2009, p. 5071-5079, Vol. 77, No. 11
0019-9567/09/$08.00+0     doi:10.1128/IAI.00457-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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