Essentiality of DevR/DosR Interaction with SigA for the Dormancy Survival Program in Mycobacterium tuberculosis

Gautam, Uma S.; Sikri, Kriti; Vashist, Atul; Singh, Varshneya; Tyagi, Jaya Sivaswami

doi:10.1128/jb.01270-13

Cited by 43 publications

(55 citation statements)

References 38 publications

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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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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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“…To demonstrate a high level of hypoxia, Mtb wild-type mice and mutants were cultured as described with minor modifications (6,26). Briefly, frozen stocks of Mtb were revived in Middlebrooks's 7H9 media supplemented with ADC and subcultured thrice to logarithmic phase (A 595 , 0.3) by shaking (aerobic).…”

Section: Transcript Measurements From Mycobacteriamentioning

confidence: 99%

“…For the hypoxic setup, cultures (from above) were aliquoted in 2-ml cryovials (Sarstedt, Newton, NC) filled to the rim with bacteria, tightly sealed, wrapped with parafilm, and incubated at 37 8 C for 35 days (hypoxic). The bacteria were lysed, and RNA was purified as described (26).…”

Section: Transcript Measurements From Mycobacteriamentioning

confidence: 99%

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

Gautam¹,

McGillivray²,

Mehra

et al. 2015

Am J Respir Cell Mol Biol

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Mycobacterium tuberculosis (Mtb) must counter hypoxia within granulomas to persist. DosR, in concert with sensor kinases DosS and DosT, regulates the response to hypoxia. Yet Mtb lacking functional DosR colonize the lungs of C57Bl/6 mice, presumably owing to the lack of organized lesions with sufficient hypoxia in that model. We compared the phenotype of the D-dosR, D-dosS, and D-dosT mutants to Mtb using C3HeB/FeJ mice, an alternate mouse model where lesions develop hypoxia. C3HeB/FeJ mice were infected via aerosol. The progression of infection was analyzed by tissue bacterial burden and histopathology. A measure of the comparative global immune responses was also analyzed. Although D-dosR and D-dosT grew comparably to wild-type Mtb, D-dosS exhibited a significant defect in bacterial burden and pathology in vivo, accompanied by ablated proinflammatory response. D-dosS retained the ability to induce DosR. The D-dosS mutant was also attenuated in murine macrophages ex vivo, with evidence of reduced expression of the proinflammatory signature. Our results show that DosS, but not DosR and DosT, is required by Mtb to survive in C3HeB/FeJ mice.The attenuation of D-dosS is not due to its inability to induce the DosR regulon, nor is it a result of the accumulation of hypoxia. That the in vivo growth restriction of D-dosS could be mimicked ex vivo suggested sensitivity to macrophage oxidative burst. Anoxic caseous centers within tuberculosis lesions eventually progress to cavities. Our results provide greater insight into the molecular mechanisms of Mtb persistence within host lungs.Keywords: Mycobacterium tuberculosis; hypoxia; response regulator; sensor kinase; latency Clinical RelevanceOur research indicates that the C3HeB/FeJ mouse model is appropriate for the study of Mycobacterium tuberculosis pathogenesis because it reveals attenuation in the D-dosS mutation. It appears that this attenuation is not the result of hypoxia in lung granulomas.

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“…A recent study has shown that sigma factors are required by some TCSs. The housekeeping sigma factor sigA participates in dormancy regulation by interacting with the TCS RR DevR [32]. DevR is a transcriptional regulator that activates the gene expression of dormant regulon and participates in the dormancy adaptation mechanisms of M. tuberculosis in response to hypoxia.…”

Section: Abstract: Drug Targets • Mycobacterium Tuberculosis • Pathogmentioning

confidence: 99%

Improved understanding of pathogenesis from protein interactions inMycobacteriumtuberculosis

Cui

He²

2014

Expert Review of Proteomics

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Comprehensive mapping and analysis of protein-protein interactions provide not only systematic approaches for dissecting the infection and survival mechanisms of pathogens but also clues for discovering new antibacterial drug targets. Protein interaction data on Mycobacterium tuberculosis have rapidly accumulated over the past several years. This review summarizes the current progress of protein interaction studies on M. tuberculosis, the causative agent of tuberculosis. These efforts improve our knowledge on the stress response, signaling regulation, protein secretion and drug resistance of the bacteria. M. tuberculosis-host protein interaction studies, although still limited, have recently opened a new door for investigating the pathogenesis of the bacteria. Finally, this review discusses the importance of protein interaction data on identifying and screening new anti-tuberculosis targets and drugs, respectively.KEYWORDS: drug targets • Mycobacterium tuberculosis • pathogen-host interaction • protein-protein interaction • stress response Mycobacterium tuberculosis, the causative agent of tuberculosis (TB), is one of the most devastating human pathogens. In 2011, there were an estimated 8.7 million new cases of TB and 1.4 million people died from TB [1]. Sophisticated regulations allow M. tuberculosis to counter host-exerted harmful environments, interfere with host signaling pathways, evade immune clearance, survive and replicate in the host. Intracellular protein-protein interactions serve important functions in many complex cellular activities, such as stress response, cell signaling, transcriptional regulation, cell division, cell wall synthesis and protein secretion. In addition, interspecies pathogen-host protein interactions help the pathogen to interfere with host pathways and then evade host immune killing. Analyzing the human protein interactions involved in M. tuberculosis infection provides insights into the infection process. All these kinds of protein interaction data provide a basis for us to understand the molecular mechanisms of M. tuberculosis pathogenesis as well as clues for anti-TB drug design (FIGURE 1). In 1998, Cole et al. sequenced the complete genome of M. tuberculosis and found that this pathogen encodes approximately 4000 genes [2]. Since then, many studies have analyzed the interactions of these genes by using computational and highthroughput experimental technologies.Protein interaction data resource of M. tuberculosis Protein-protein interactions include physical interactions and functional interactions, in which physical interactions refer to the direct binding of two proteins and functional interactions mean these proteins are of functional relevance, for example, they are components of a same cell pathway. Unless specified otherwise, protein interactions in this review mean physical interactions. Obtaining protein-protein interaction data is important to elucidate the functions and mechanisms of this interaction in different cellular processes. The recent advances in the computa...

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Essentiality of DevR/DosR Interaction with SigA for the Dormancy Survival Program in Mycobacterium tuberculosis

Cited by 43 publications

References 38 publications

Mycobacterium tuberculosis Transcription Machinery: Ready To Respond to Host Attacks

Mycobacterium tuberculosis Transcription Machinery: Ready To Respond to Host Attacks

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

Improved understanding of pathogenesis from protein interactions inMycobacteriumtuberculosis

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