Posttreatment reactivation of tuberculosis in mice caused by Mycobacterium tuberculosis disrupted in mce1R.
BACKGROUND
The reactivation of tuberculosis arises in persons who are latently infected and in those who have been previously treated. The mechanism of the reactivation of tuberculosis in either situation is not well understood. A 13-gene mce1 operon of Mycobacterium tuberculosis was previously shown to be associated with latent infection in mice and may also play a role in reactivation.


METHODS
We tested mce1 operon M. tuberculosis mutants in a Cornell mouse model to examine disease progression and reactivation.


RESULTS
In BALB/c mice, the wild-type, mce1 operon mutant, and mce1R (negative transcriptional regulator of the mce1 operon) mutant M. tuberculosis strains were equally susceptible to orally administered isoniazid and pyrazinamide. However, after cessation of the treatment, the mce1R mutant rapidly and progressively proliferated in mouse lungs and spleens, whereas the other strains remained latent. The reactivation of the mce1R mutant was associated with disease progression in the mouse lungs.


CONCLUSIONS
This observation demonstrates that the constitutive expression of the mce1 genes by M. tuberculosis in the latent state can cause a reactivation of tuberculosis. The constitutive expression of the mce1 genes in the mce1R mutant may allow this mutant to maintain its lipid metabolism, enabling it to survive long-term and proliferate inside granulomas.
Cheigh
Chan-Ick
CI
Division of Infectious Diseases, School of Public Health, University of California-Berkeley, CA 94720, USA.
Senaratne
Ryan
R
Uchida
Yujiro
Y
Casali
Nicola
N
Kendall
Lon V
LV
Riley
Lee W
LW
D000818:Animals; D000995:Antitubercular Agents / Q000627:therapeutic use; D001426:Bacterial Proteins / Q000235:genetics*; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D007538:Isoniazid / Q000627:therapeutic use; D008168:Lung / Q000382:microbiology / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D009154:Mutation; D009169:Mycobacterium tuberculosis / Q000187:drug effects / Q000235:genetics / Q000254:growth & development* / Q000472:pathogenicity; D009876:Operon / Q000235:genetics; D011718:Pyrazinamide / Q000627:therapeutic use; D013997:Time Factors; D014397:Tuberculosis, Pulmonary / Q000188:drug therapy* / Q000382:microbiology
D000995:Antitubercular Agents; D001426:Bacterial Proteins; C473802:mammalian cell entry protein Mce1A, Mycobacterium tuberculosis; D011718:Pyrazinamide; D007538:Isoniazid