DosS Is Required for the Complete Virulence of <i>Mycobacterium tuberculosis</i> in Mice with Classical Granulomatous Lesions

Gautam, Uma S.; McGillivray, Amanda; Mehra, Smriti; Didier, Peter J.; Midkiff, Cecily C.; Kissee, Ryan S.; Golden, Nadia; Álvarez, Xavier; Niu, Tianhua; Rengarajan, Jyothi; Sherman, David R.; Kaushal, Deepak

doi:10.1165/rcmb.2014-0230oc

Cited by 50 publications

(72 citation statements)

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“…However, as other research groups have demonstrated, the standard mouse model of infection may not be suitable for teasing apart differences between strains based solely around DosR expression (57)(58)(59)(60). The granuloma-like cellular aggregations that form in the normal mouse lung appear not to develop areas of hypoxia; thus, any benefit to the bacteria that may arise due to continuous DosR regulon expression during the early phases of hypoxia development, for example, may not be observable within this model (61,62).…”

Section: Fig 6 the Dost Defect In Beijing Isolates Has No Impact On Tmentioning

confidence: 97%

“…The granuloma-like cellular aggregations that form in the normal mouse lung appear not to develop areas of hypoxia; thus, any benefit to the bacteria that may arise due to continuous DosR regulon expression during the early phases of hypoxia development, for example, may not be observable within this model (61,62). In this regard, rabbits, guinea pigs, monkeys or the Kramnik mouse model may be more informative in future efforts aimed at comparing the effect of the Beijing versus non-Beijing DosR phenotypes on pathogenesis (57,59,60,62). The early delayedgrowth phenotype seen with the dosRS KO mutant suggests that this strain may be at a disadvantage early on after T-cell-mediated immunity develops in the lung.…”

Section: Fig 6 the Dost Defect In Beijing Isolates Has No Impact On Tmentioning

confidence: 99%

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Unique Regulation of the DosR Regulon in the Beijing Lineage of Mycobacterium tuberculosis

et al. 2017

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The DosR regulon, a set of 48 genes normally expressed in Mycobacterium tuberculosis under conditions that inhibit aerobic respiration, is controlled via the DosR-DosS/DosT two-component system. While the regulon requires induction in most M. tuberculosis isolates, for members of the Beijing lineage, its expression is uncoupled from the need for signaling. In our attempts to understand the mechanistic basis for this uncoupling in the Beijing background, we previously reported the identification of two synonymous single-nucleotide polymorphisms (SNPs) within the adjacent Rv3134c gene. In the present study, we have interrogated the impact of these SNPs on dosR expression in wild-type strains, as well as a range of dosRdosS-dosT mutants, for both Beijing and non-Beijing M. tuberculosis backgrounds. In this manner, we have unequivocally determined that the C601T dosR promoter SNP is the sole requirement for the dramatic shift in the pattern of DosR regulon expression seen in this globally important lineage. Interestingly, we also show that DosT is completely nonfunctional within these strains. Thus, a complex series of evolutionary steps has led to the present-day Beijing DosR phenotype that, in turn, potentially confers a fitness advantage in the face of some form of host-associated selective pressure.IMPORTANCE Mycobacterium tuberculosis strains of the Beijing lineage have been described as being of enhanced virulence compared to other lineages, and in certain regions, they are associated with the dramatic spread of multidrug-resistant tuberculosis (TB). In terms of trying to understand the functional basis for these broad epidemiological phenomena, it is interesting that, in contrast to the other major lineages, the Beijing strains all constitutively overexpress members of the DosR regulon. Here, we identify the mutational events that led to the evolution of this unique phenotype. In addition, our work highlights the fact that important phenotypic differences exist between distinct M. tuberculosis lineages, with the potential to impact the efficacy of diagnosis, vaccination, and treatment programs.KEYWORDS Tuberculosis, DosR regulon, strain variation, evolution, Mycobacterium tuberculosis D espite being an ancient disease, human tuberculosis (TB) resulting from infection with Mycobacterium tuberculosis still remains a leading cause of death worldwide as a consequence of multiple contributing factors, including drug resistance, HIV coinfection, and inadequate access to high-quality health care (1). Furthermore, recent evidence suggests that the level of genetic diversity that exists among distinct M. tuberculosis isolates was previously underestimated and has the potential to impact pathogenicity, as well as to limit the effectiveness of current diagnostic and therapeutic interventions (2-4).

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Section: Fig 6 the Dost Defect In Beijing Isolates Has No Impact On Tmentioning

confidence: 97%

Section: Fig 6 the Dost Defect In Beijing Isolates Has No Impact On Tmentioning

confidence: 99%

Unique Regulation of the DosR Regulon in the Beijing Lineage of Mycobacterium tuberculosis

et al. 2017

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“…DosS acts as a redox sensor and DosT as a hypoxia sensor, illustrating the integration and differentiation of M. tuberculosis stress responses (105). Genetic disruption of the dosRST TCS results in reduced bacterial survival under low-oxygen conditions, in mouse models that develop hypoxic lesions, and in a nonhuman primate macaque model of infection (106)(107)(108)(109).…”

Section: Nonessential Tcss and Tfs: Special Forces Of The Stress Respmentioning

confidence: 99%

Mycobacterium tuberculosis Transcription Machinery: Ready To Respond to Host Attacks

2016

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Regulating responses to stress is critical for all bacteria, whether they are environmental, commensal, or pathogenic species. For pathogenic bacteria, successful colonization and survival in the host are dependent on adaptation to diverse conditions imposed by the host tissue architecture and the immune response. Once the bacterium senses a hostile environment, it must enact a change in physiology that contributes to the organism's survival strategy. Inappropriate responses have consequences; hence, the execution of the appropriate response is essential for survival of the bacterium in its niche. Stress responses are most often regulated at the level of gene expression and, more specifically, transcription. This minireview focuses on mechanisms of regulating transcription initiation that are required by Mycobacterium tuberculosis to respond to the arsenal of defenses imposed by the host during infection. In particular, we highlight how certain features of M. tuberculosis physiology allow this pathogen to respond swiftly and effectively to host defenses. By enacting highly integrated and coordinated gene expression changes in response to stress, M. tuberculosis is prepared for battle against the host defense and able to persist within the human population.T he survival of any organism relies on its ability to sense and respond to changes in its environment. For bacteria, stress responses are primarily mediated through the regulation of gene expression. By integrating multiple molecular approaches to gene regulation, pathogenic bacteria are able to orchestrate conditionspecific patterns that promote survival and pathogenesis in the face of a strong immune response. This minireview focuses on mechanisms of transcription regulation required for stress responses in one of the most successful and deadly pathogens in the world, Mycobacterium tuberculosis. M. tuberculosis has coexisted with humans for Ͼ50,000 years (1) and continues to cause more than 1.5 million deaths a year (2). The coevolution of M. tuberculosis with the human host response to infection has resulted in a pathogen that is specialized for long-term infection in people. Tuberculosis is a complex disease that requires the bacteria to multiply within phagocytes, survive extracellularly in hypoxic and necrotic granulomas, and endure a robust immune response to persist in the host. During infection, the host immune response restrains M. tuberculosis from proliferating by imposing a battery of defenses, including reactive oxygen and nitrogen stress, hypoxia, acid stress, genotoxic stress, cell surface stress, and starvation (3). Despite this onslaught of attacks, M. tuberculosis is able to persist for the lifetime of the host, indicating that this pathogen has highly effective molecular mechanisms to resist host-inflicted damage. In order to enact these defenses and facilitate this specialized lifestyle, M. tuberculosis executes a complex, interconnected web of stress responses that rely on changes in gene expression. In fact, M. tuberculosis is well suite...

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“…DosS and DosT have been shown to play an important role in the transition from the replicating state to NRP (15). Recently, Gautam et al (16) showed that DosS has a critical role in survival of M. tuberculosis in C3HeB/FeJ mice, whereas deletion of DosR and DosT gave rise to a growth curve comparable with that of wild-type M. tuberculosis. Kumar et al (17) demonstrated the importance of DosS by showing that induction of M. tuberculosis dormancy by CO depended primarily on sensing by DosS.…”

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Distal Hydrogen-bonding Interactions in Ligand Sensing and Signaling by Mycobacterium tuberculosis DosS

Basudhar

Madrona

Yukl

et al. 2016

Journal of Biological Chemistry

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Mycobacterium tuberculosis DosS is critical for the induction of M. tuberculosis dormancy genes in response to nitric oxide (NO), carbon monoxide (CO), or hypoxia. These environmental stimuli, which are sensed by the DosS heme group, result in autophosphorylation of a DosS His residue, followed by phosphotransfer to an Asp residue of the response regulator DosR. To clarify the mechanism of gaseous ligand recognition and signaling, we investigated the hydrogen-bonding interactions of the iron-bound CO and NO ligands by site-directed mutagenesis of Glu-87 and His-89. Autophosphorylation assays and molecular dynamics simulations suggest that Glu-87 has an important role in ligand recognition, whereas His-89 is essential for signal transduction to the kinase domain, a process for which Arg-204 is important. Mutation of Glu-87 to Ala or Gly rendered the protein constitutively active as a kinase, but with lower autophosphorylation activity than the wild-type in the Fe(II) and the Fe(II)-CO states, whereas the E87D mutant had little kinase activity except for the Fe(II)-NO complex. The H89R mutant exhibited attenuated autophosphorylation activity, although the H89A and R204A mutants were inactive as kinases, emphasizing the importance of these residues in communication to the kinase core. Resonance Raman spectroscopy of the wild-type and H89A mutant indicates the mutation does not alter the heme coordination number, spin state, or porphyrin deformation state, but it suggests that interdomain interactions are disrupted by the mutation. Overall, these results confirm the importance of the distal hydrogen-bonding network in ligand recognition and communication to the kinase domain and reveal the sensitivity of the system to subtle differences in the binding of gaseous ligands.Tuberculosis, an airborne disease caused by Mycobacterium tuberculosis, is believed to have infected nearly 1 out of 3 people worldwide (1). Like any infection, tuberculosis leads to a host immune response resulting in recruitment of lymphocytes and macrophages (2). This process is associated with high levels of NO and CO produced by inducible nitric-oxide synthase and heme oxygenase-1 (HO-1), respectively, as part of the defense mechanism of macrophages (3-5). The ability of M. tuberculosis to successfully survive within the host for years in a clinically undetectable dormant state known as non-replicating persistence (NRP), 3 in which it is resistant to most of the currently available treatments, makes it of paramount importance to elucidate this defense strategy (6). The mechanism of NRP is not fully understood; however, hypoxia (7, 8), high CO and NO levels (5, 9), nutrient deprivation (10), and the pH of the microenvironment (11) are among the factors leading to NRP. It has been shown that NRP can initiate changes in energy metabolism and cellular signaling pathways that lead to M. tuberculosis growth arrest. Decreased cellular activity is believed to be the main reason for the long term treatment protocols required to eradicate the bacteria. Mo...

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DosS Is Required for the Complete Virulence of Mycobacterium tuberculosis in Mice with Classical Granulomatous Lesions

Cited by 50 publications

References 50 publications

Unique Regulation of the DosR Regulon in the Beijing Lineage of Mycobacterium tuberculosis

Unique Regulation of the DosR Regulon in the Beijing Lineage of Mycobacterium tuberculosis

Mycobacterium tuberculosis Transcription Machinery: Ready To Respond to Host Attacks

Distal Hydrogen-bonding Interactions in Ligand Sensing and Signaling by Mycobacterium tuberculosis DosS

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