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, Chinnaswamy Jagannath

Research output: Contribution to journalArticle

43 Scopus citations

Abstract

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 (ΔfbpA) was tested for its ability to immunize mice. The ΔfbpB mutant was attenuated in mice after intravenous or aerosol infection, while replication of the ΔfbpB mutant was similar to that of the wild type. Complementation of the fbpA gene in ΔfbpA restored its ability to grow in the lungs of mice. The ΔfbpA mutant induced a stronger expression of pulmonary mRNA messages in mice for tumor necrosis factor alpha, interleukin-1 beta (IL-1β), 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 ΔfbpA both induced NO in macrophages and were equally susceptible to NO donors, although ΔfbpA 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 ΔfbpA infection, resisted a challenge with virulent M. tuberculosis. Mice subcutaneously immunized with ΔfbpA 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 ΔfbpA mutant was thus attenuated, unlike ΔfbpB, but was also vaccinogenic against tuberculosis. Attenuation was incomplete, however, since ΔfbpA 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.

Original languageEnglish (US)
Pages (from-to)7084-7095
Number of pages12
JournalInfection and Immunity
Volume72
Issue number12
DOIs
StatePublished - Dec 2004
Externally publishedYes

ASJC Scopus subject areas

  • Parasitology
  • Microbiology
  • Immunology
  • Infectious Diseases

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