Posttreatment Reactivation of Tuberculosis in Mice Caused byMycobacterium tuberculosisDisrupted inmce1R

Abstract

Background Reactivation tuberculosis (TB) arises from those who are latently infected or from those who have been previously treated. The mechanism of reactivation TB in either situation is not well understood. A 13-gene mce1 operon of M. 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 Mycobacterium 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 spleen, while 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 latent state can cause reactivation TB. 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.

Preclinical and Clinical Evidence of Mycobacterium tuberculosis Persistence in the Hypoxic Niche of Bone Marrow Mesenchymal Stem Cells after Therapy

“…Second, the mice were treated with INH-PZA treatment for 90 days ( Figure 1A), as previously described. 18,19 Day 60 after infection was chosen as the start day for INH-PZA treatment, because peak CFU and granuloma formation was typically observed by day 60 after infection in our model, which is consistent with previous reports. 20,21 Third, the animals were euthanized after 90 days of drug treatment, and BM cells were subjected to flow cytometry and confocal microscopy detection of the GFP-positive CD271 þ cell population.…”

“…The Cornell model that was used in the study 18,27 is one of the many variants, in which we used an i.v. route of MTB infection.…”

“…We used a variant of the Cornell model, 18,19 in which MTB infection was introduced by the i.v. route, and mice were treated with isoniazid (INH) and pyrazinamide (PZA) to achieve organ sterility.…”

“…route, and mice were treated with isoniazid (INH) and pyrazinamide (PZA) to achieve organ sterility. 18 Briefly, pathogen-free, 6-week-old female BALB/c mice were obtained from the National Institute of Nutrition (Hyderabad, India). They were housed within a biosafety level 3 within microisolator cages, and fed pelleted food and water ad libitum.…”

Mycobacterium tuberculosis DinG Is a Structure-specific Helicase That Unwinds G4 DNA

“…Our study demonstrates the existence of G4 structures in M. tuberculosis cells. The genes that are encoded by the mce1R operon play a crucial role in the persistence of M. tuberculosis in the murine model (78). We demonstrate that G-rich sequences that are present in the promoter region of the mce1R gene indeed fold into G4 structure, suggesting that the G4 structure may regulate the expression of mce1R.…”