Inhibiting the stringent response blocks entry into quiescence and reduces persistence.

The stringent response enables () to shut down its replication and metabolism under various stresses. Here we show that lacking the stringent response enzyme Rel was unable to slow its replication rate during nutrient starvation. Metabolomics analysis revealed that the nutrient-starved -deficient strain had increased metabolism similar to that of exponentially growing wild-type bacteria in nutrient-rich broth, consistent with an inability to enter quiescence.

TLR2-Modulating Lipoproteins of the Mycobacterium tuberculosis Complex Enhance the HIV Infectivity of CD4+ T Cells.

Co-infection with Mycobacterium tuberculosis accelerates progression from HIV to AIDS. Our previous studies showed that M. tuberculosis complex, unlike M.

Rv1894c is a novel hypoxia-induced nitronate monooxygenase required for Mycobacterium tuberculosis virulence.

Tuberculosis is difficult to cure, requiring a minimum of 6 months of treatment with multiple antibiotics. Small numbers of organisms are able to tolerate the antibiotics and persist in the lungs of infected humans, but they still require some metabolic activity to survive. We studied the role of the hypoxia-induced Rv1894c gene in Mycobacterium tuberculosis virulence in guinea pigs, which develop hypoxic, necrotic granulomas histologically resembling those in humans and found this gene to be necessary for full bacillary growth and survival.

Strain-dependent CNS dissemination in guinea pigs after Mycobacterium tuberculosis aerosol challenge.

Clinical reports suggest an association of distinct Mycobacterium tuberculosis strains with CNS disease. We therefore examined CNS dissemination by different laboratory strains (two M. tuberculosis H37Rv, one CDC1551) in a guinea pig aerosol infection model.

The stringent response is required for full virulence of Mycobacterium tuberculosis in guinea pigs.

During human latent tuberculosis infection, Mycobacterium tuberculosis likely resides within the nutrient‐starved environment of caseous lung granulomas. The stringent response alarmone (p)ppGpp is synthesized by Rel in response to nutrient starvation, thus enabling tubercle bacilli to restrict growth and shut down metabolism in a coordinated fashion. In this study, we investigated the virulence of a rel‐deficient M.

The impact of mouse passaging of Mycobacterium tuberculosis strains prior to virulence testing in the mouse and guinea pig aerosol models.

Background: It has been hypothesized that the virulence of lab-passaged Mycobacterium tuberculosis and recombinant M. tuberculosis mutants might be reduced due to multiple in vitro passages, and that virulence might be augmented by passage of these strains through mice before quantitative virulence testing in the mouse or guinea pig aerosol models.

Methodology/principal Findings: By testing three M.

Biphasic kill curve of isoniazid reveals the presence of drug-tolerant, not drug-resistant, Mycobacterium tuberculosis in the guinea pig.

The marked reduction in the potent early bactericidal activity of isoniazid during the initial phase of antituberculosis (anti-TB) therapy has been attributed not only to the depletion of logarithmically growing bacilli but also to the emergence of isoniazid resistance. We studied the anti-TB activity of isoniazid and its ability to select for drug-resistant mutant strains in guinea pigs, in which the histopathology of TB closely resembles that of human TB. Prior mouse passage did not appear to enhance the virulence of Mycobacterium tuberculosis in guinea pigs.

Role of the dosR-dosS two-component regulatory system in Mycobacterium tuberculosis virulence in three animal models.

The Mycobacterium tuberculosis dosR gene (Rv3133c) is part of an operon, Rv3134c-Rv3132c, and encodes a response regulator that has been shown to be upregulated by hypoxia and other in vitro stress conditions and may be important for bacterial survival within granulomatous lesions found in tuberculosis. DosR is activated in response to hypoxia and nitric oxide by DosS (Rv3132c) or DosT (Rv2027c). We compared the virulence levels of an M.

Metronidazole lacks activity against Mycobacterium tuberculosis in an in vivo hypoxic granuloma model of latency.

During human latent tuberculosis (TB) infection, dormant bacilli putatively reside within the hypoxic environment of caseating lung granulomas. The anaerobic drug metronidazole has antituberculous activity under hypoxic conditions in vitro but lacks activity against murine TB. In the present study, we used the hypoxia marker pimonidazole to demonstrate the presence of hypoxia in a novel in vivo granuloma model of Mycobacterium tuberculosis latency.

Accelerated detection of Mycobacterium tuberculosis genes essential for bacterial survival in guinea pigs, compared with mice.

Background: Mouse and guinea pig models have been used to identify Mycobacterium tuberculosis mutants attenuated for survival. However, unlike mice, M. tuberculosis-infected guinea pigs form caseating granulomas, which may simulate human disease more closely.

Synergy among differentially regulated repressors of the ribonucleotide diphosphate reductase genes of Saccharomyces cerevisiae.

The Ssn6/Tup1 general repression complex represses transcription of a number of regulons through recruitment by regulon-specific DNA-binding repressors. Rox1 and Mot3 are Ssn6/Tup1-recruiting, DNA-binding proteins that repress the hypoxic genes, and Rfx1 is a Ssn6/Tup1-recruiting, a DNA-binding protein that represses the DNA damage-inducible genes. We previously reported that Rox1 and Mot3 functioned synergistically to repress a subset of the hypoxic genes and that this synergy resulted from an indirect interaction through Ssn6.

Combinatorial repression of the hypoxic genes of Saccharomyces cerevisiae by DNA binding proteins Rox1 and Mot3.

The hypoxic genes of Saccharomyces cerevisiae are transcriptionally repressed during aerobic growth through recruitment of the Ssn6/Tup1 general repression complex by the DNA binding protein Rox1. A second DNA binding protein Mot3 enhances repression of some hypoxic genes. Previous studies characterized the role of Mot3 at the hypoxic ANB1 gene as promoting synergy among one Mot3 site and two Rox1 sites comprising operator A of that gene.

Recruitment of Tup1-Ssn6 by yeast hypoxic genes and chromatin-independent exclusion of TATA binding protein.

The Tup1-Ssn6 general repression complex in Saccharomyces cerevisiae represses a wide variety of regulons. Regulon-specific DNA binding proteins recruit the repression complex, and their synthesis, activity, or localization controls the conditions for repression. Rox1 is the hypoxic regulon-specific protein, and a second DNA binding protein, Mot3, augments repression at tightly controlled genes.