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Infection and Immunity, December 2004, p. 7084-7095, Vol. 72, No. 12
0019-9567/04/$08.00+0     DOI: 10.1128/IAI.72.12.7084-7095.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

A Mutant of Mycobacterium tuberculosis H37Rv That Lacks Expression of Antigen 85A Is Attenuated in Mice but Retains Vaccinogenic Potential

Robert H. Copenhaver, Eliud Sepulveda, Lisa Y. Armitige, Jeffrey K. Actor, Audrey Wanger, Steven J. Norris, Robert L. Hunter, and Chinnaswamy Jagannath*

Department of Pathology and Laboratory Medicine, University of Texas Health Sciences Center, Houston, Texas

Received 25 February 2004/ Returned for modification 2 April 2004/ Accepted 23 July 2004

The fbpA and fbpB genes encoding the 85A and 85B proteins of Mycobacterium tuberculosis H37Rv, respectively, were disrupted, the mutants were examined for their ability to survive, and the strain lacking 85A ({Delta}fbpA) was tested for its ability to immunize mice. The {Delta}fbpA mutant was attenuated in mice after intravenous or aerosol infection, while replication of the {Delta}fbpB mutant was similar to that of the wild type. Complementation of the fbpA gene in {Delta}fbpA restored its ability to grow in the lungs of mice. The {Delta}fbpA mutant induced a stronger expression of pulmonary mRNA messages in mice for tumor necrosis factor alpha, interleukin-1 beta (IL-1ß), gamma interferon, IL-6, IL-2, and inducible nitric oxide (NO) synthase, which led to its decline, while H37Rv persisted despite strong immune responses. H37Rv and {Delta}fbpA both induced NO in macrophages and were equally susceptible to NO donors, although {Delta}fbpA was more susceptible in vitro to peroxynitrite and its growth was enhanced by NO inhibitors in mice and macrophages. Aerosol-infected mice, which cleared a low-dose {Delta}fbpA infection, resisted a challenge with virulent M. tuberculosis. Mice subcutaneously immunized with {Delta}fbpA or Mycobacterium bovis BCG and challenged with M. tuberculosis also showed similar levels of protection, marked by a reduction in the growth of challenged M. tuberculosis. The {Delta}fbpA mutant was thus attenuated, unlike {Delta}fbpB, but was also vaccinogenic against tuberculosis. Attenuation was incomplete, however, since {Delta}fbpA revived in normal mice after 370 days, suggesting that revival was due to immunosenescence but not compensation by the fbpB or fbpC gene. Antigen 85A thus affects susceptibility to peroxynitrite in M. tuberculosis and appears to be necessary for its optimal growth in mice.

* Corresponding author. Mailing address: MSB 2200, Dept. of Pathology and Laboratory Medicine, UTHSC, 6431 Fannin, Houston, TX 77030. Phone: (713) 500-5353. Fax: (713) 500-0730. E-mail: chinnaswamy.jagannath{at}uth.tmc.edu.

Editor: J. D. Clements

Infection and Immunity, December 2004, p. 7084-7095, Vol. 72, No. 12
0019-9567/04/$08.00+0     DOI: 10.1128/IAI.72.12.7084-7095.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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