Dim mutants of mycobacteria and use thereof

Details Dim mutants of mycobacteria and use thereof Dim mutants of mycobacteria and use thereof

1999-07-09

2001-09-18

Swart, Rodney P. (Department: 1645)

Drug, bio-affecting and body treating compositions

Antigen, epitope, or other immunospecific immunoeffector

Recombinant or stably-transformed bacterium encoding one or...

C424S248100, C435S007400, C435S007600, C435S007910, C435S069100, C435S183000, C435S252300, C435S253100

Reexamination Certificate

active

06290966

ABSTRACT:

BACKGROUND OF THE INVENTION
Tuberculosis is the leading cause of death in the world due to a single bacterial infection (27). Despite its enormous burden on world health, little is known about the molecular mechanisms of
M. tuberculosis
pathogenesis. Bacterial multiplication and concomitant tissue damage within an infected host, including experimentally infected mice, occurs primarily in the lungs—the favored niche of
M. tuberculosis
(28). Although it has been postulated that the distinctive cell wall of
M. tuberculosis
is important for virulence, rigorous genetic proof has been lacking. Using signature tagged mutagenesis, the inventors have isolated three attenuated
M. tuberculosis
mutants that are unable to synthesize or transport a complex, cell wall-associated lipid known as dimycoserosalphthiocerol (DIM). Two mutants of the present invention have transposon insertions affecting genes implicated in DIM synthesis, while the third mutant has a disruption of a gene encoding a large transmembrane protein required for DIM secretion. Surprisingly, synthesis and transport of this complex lipid is only required for growth in the lung; all three mutants are unaffected for growth in the liver and spleen.
M. tuberculosis
mutants deficient for DIM synthesis are attractive candidates for the development of a live, attenuated vaccine.
SUMMARY OF THE INVENTION
The present invention provides novel recombinant mutant strains of mycobacteria that are deficient for the synthesis or transport of dimycoserosalphthiocerol (“DIM”). The present invention also provides a method of producing a recombinant mutant mycobacterium that is deficient for synthesis or transport of dimycoserosalphthiocerol, comprising mutating a nucleic acid responsible for the synthesis or transport of dimycoserosalphthiocerol. Methods of producing the recombinant mutant mycobacterium of the present invention include, for example, illegitimate recombination, legitimate recombination and transposon insertion. Further provided by the present invention is a vaccine using the recombinant mutant mycobacterium of the present invention, as well as a method of treating or preventing tuberculosis in a subject comprising administering the vaccine of the present invention in an amount effective to treat or prevent tuberculosis in the subject.
The present invention is described in the following Detailed Description of the Invention which is set forth to aid in the understanding of the invention, and should not be construed to limit in any way the scope of the invention as defined in the claims which follow thereafter.


REFERENCES:
Azad, A.K., et al, “Gene knockout reveals a novel gene cluster for the synthesis of a class of cell wall lipids unique to pathogenic mycobacteria”, The Journal of Biological Chemistry, vol. 272, No. 27, pp. 16741-16745, Jul. 1997.*
Wiegeshaus, E.H., et al, “Evaluation of the protective potency of new tuberculosis vaccines”, Reviews of Infectious Diseases, vol. 11, Suppl. 2, pp. S484-S490, Mar. 1989.

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