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Infection and Immunity, June 1999, p. 2941-2950, Vol. 67, No. 6
0019-9567/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Molecular Characterization and Human T-Cell Responses to a Member of a Novel Mycobacterium tuberculosis mtb39 Gene Family

Davin C. Dillon,1,* Mark R. Alderson,1 Craig H. Day,1 David M. Lewinsohn,2 Rhea Coler,2 Teresa Bement,1 Antonio Campos-Neto,2 Y. A. W. Skeiky,1 Ian M. Orme,3 Alan Roberts,3 Sean Steen,1 Wilfried Dalemans,4 Roberto Badaro,5 and Steven G. Reed1,2,6

Corixa Corporation1 and Infectious Disease Research Institute,2 Seattle, Washington 98104; Department of Microbiology, Colorado State University, Fort Collins, Colorado 805233; SmithKline Beecham Biologicals, Rixensart, Belgium4; Federal University of Bahia, Salvador, Brazil5; and Department of Pathobiology, University of Washington, Seattle, Washington 981956

Received 11 August 1998/Returned for modification 16 September 1998/Accepted 22 March 1999

We have used expression screening of a genomic Mycobacterium tuberculosis library with tuberculosis (TB) patient sera to identify novel genes that may be used diagnostically or in the development of a TB vaccine. Using this strategy, we have cloned a novel gene, termed mtb39a, that encodes a 39-kDa protein. Molecular characterization revealed that mtb39a is a member of a family of three highly related genes that are conserved among strains of M. tuberculosis and Mycobacterium bovis BCG but not in other mycobacterial species tested. Immunoblot analysis demonstrated the presence of Mtb39A in M. tuberculosis lysate but not in culture filtrate proteins (CFP), indicating that it is not a secreted antigen. This conclusion is strengthened by the observation that a human T-cell clone specific for purified recombinant Mtb39A protein recognized autologous dendritic cells infected with TB or pulsed with purified protein derivative (PPD) but did not respond to M. tuberculosis CFP. Purified recombinant Mtb39A elicited strong T-cell proliferative and gamma interferon responses in peripheral blood mononuclear cells from 9 of 12 PPD-positive individuals tested, and overlapping peptides were used to identify a minimum of 10 distinct T-cell epitopes. Additionally, mice immunized with mtb39a DNA have shown increased protection from M. tuberculosis challenge, as indicated by a reduction of bacterial load. The human T-cell responses and initial animal studies provide support for further evaluation of this antigen as a possible component of a subunit vaccine for M. tuberculosis.

* Corresponding author. Mailing address: Corixa Corporation, 1124 Columbia St., Suite 200, Seattle, WA 98104. Phone: (206) 754-5701. Fax: (206) 754-5715. E-mail: dillon{at}corixa.com.

Infection and Immunity, June 1999, p. 2941-2950, Vol. 67, No. 6
0019-9567/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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