scholarly journals The Mycobacterium tuberculosis DosR Regulon Assists in Metabolic Homeostasis and Enables Rapid Recovery from Nonrespiring Dormancy

2009 ◽  
Vol 192 (6) ◽  
pp. 1662-1670 ◽  
Author(s):  
Rachel L. Leistikow ◽  
Russell A. Morton ◽  
Iona L. Bartek ◽  
Isaac Frimpong ◽  
Karleen Wagner ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Mycobacterium Tuberculosis ◽  
Energy Levels ◽  
Redox Balance ◽  
Bacterial Metabolism ◽  
Aerobic Respiration ◽  
Latently Infected ◽  
The Face ◽  
Anaerobic Dormancy ◽  
Dosr Regulon

ABSTRACT Mycobacterium tuberculosis survives in latently infected individuals, likely in a nonreplicating or dormancy-like state. The M. tuberculosis DosR regulon is a genetic program induced by conditions that inhibit aerobic respiration and prevent bacillus replication. In this study, we used a mutant incapable of DosR regulon induction to investigate the contribution of this regulon to bacterial metabolism during anaerobic dormancy. Our results confirm that the DosR regulon is essential for M. tuberculosis survival during anaerobic dormancy and demonstrate that it is required for metabolic processes that occur upon entry into and throughout the dormant state. Specifically, we showed that regulon mechanisms shift metabolism away from aerobic respiration in the face of dwindling oxygen availability and are required for maintaining energy levels and redox balance as the culture becomes anaerobic. We also demonstrated that the DosR regulon is crucial for rapid resumption of growth once M. tuberculosis exits an anaerobic or nitric oxide-induced nonrespiring state. In summary, the DosR regulon encodes novel metabolic mechanisms essential for M. tuberculosis to survive in the absence of respiration and to successfully transition rapidly between respiring and nonrespiring conditions without loss of viability.

scholarly journals Inhibition of Respiration by Nitric Oxide Induces a Mycobacterium tuberculosis Dormancy Program

2003 ◽  
Vol 198 (5) ◽  
pp. 705-713 ◽  
Author(s):  
Martin I. Voskuil ◽  
Dirk Schnappinger ◽  
Kevin C. Visconti ◽  
Maria I. Harrell ◽  
Gregory M. Dolganov ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Mycobacterium Tuberculosis ◽  
Latent Tuberculosis ◽  
No Synthase ◽  
No Production ◽  
Respiratory Pathway ◽  
Latently Infected ◽  
Synthase Inhibitor

An estimated two billion persons are latently infected with Mycobacterium tuberculosis. The host factors that initiate and maintain this latent state and the mechanisms by which M. tuberculosis survives within latent lesions are compelling but unanswered questions. One such host factor may be nitric oxide (NO), a product of activated macrophages that exhibits antimycobacterial properties. Evidence for the possible significance of NO comes from murine models of tuberculosis showing progressive infection in animals unable to produce the inducible isoform of NO synthase and in animals treated with a NO synthase inhibitor. Here, we show that O2 and low, nontoxic concentrations of NO competitively modulate the expression of a 48-gene regulon, which is expressed in vivo and prepares bacilli for survival during long periods of in vitro dormancy. NO was found to reversibly inhibit aerobic respiration and growth. A heme-containing enzyme, possibly the terminal oxidase in the respiratory pathway, likely senses and integrates NO and O2 levels and signals the regulon. These data lead to a model postulating that, within granulomas, inhibition of respiration by NO production and O2 limitation constrains M. tuberculosis replication rates in persons with latent tuberculosis.

scholarly journals Unique Roles of DosT and DosS in DosR Regulon Induction and Mycobacterium tuberculosis Dormancy

2009 ◽  
Vol 77 (8) ◽  
pp. 3258-3263 ◽  
Author(s):  
Ryan W. Honaker ◽  
Rachel L. Leistikow ◽  
Iona L. Bartek ◽  
Martin I. Voskuil
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Latent Infection ◽  
Transcriptional Regulator ◽  
Wild Type ◽  
Hypoxic Conditions ◽  
Sensor Kinases ◽  
The Individual ◽  
Anaerobic Dormancy ◽  
Dosr Regulon

ABSTRACT In Mycobacterium tuberculosis, the sensor kinases DosT and DosS activate the transcriptional regulator DosR, resulting in the induction of the DosR regulon, which is important for anaerobic survival and perhaps latent infection. The individual and collective roles of these sensors have been postulated biochemically, but their roles in vivo have remained unclear. This work demonstrates distinct and additive roles for each sensor during anaerobic dormancy. Both sensors are necessary for wild-type levels of DosR regulon induction, and concomitantly, full induction of the regulon is required for wild-type anaerobic survival. In the anaerobic model, DosT plays an early role, responding to hypoxia. DosT then induces the regulon and with it DosS, which sustains and further induces the regulon. DosT then loses its functionality as oxygen becomes limited, and DosS alone maintains induction of the genes from that point forward. Thus, M. tuberculosis has evolved a system whereby it responds to hypoxic conditions in a stepwise fashion as it enters an anaerobic state.

scholarly journals Inducible nitric oxide synthase in pulmonary alveolar macrophages from patients with tuberculosis.

1996 ◽  
Vol 183 (5) ◽  
pp. 2293-2302 ◽  
Author(s):  
S Nicholson ◽  
M da G Bonecini-Almeida ◽  
J R Lapa e Silva ◽  
C Nathan ◽  
Q W Xie ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Mycobacterium Tuberculosis ◽  
Nitric Oxide Synthase ◽  
Bronchoalveolar Lavage ◽  
Inducible Nitric Oxide Synthase ◽  
Alveolar Macrophages ◽  
Mononuclear Phagocytes ◽  
Mycobacterium Tuberculosis Infection ◽  
Oxide Synthase ◽  
Inducible Nitric Oxide

The high-output pathway of nitric oxide production helps protect mice from infection by several pathogens, including Mycobacterium tuberculosis. However, based on studies of cells cultured from blood, it is controversial whether human mononuclear phagocytes can express the corresponding inducible nitric oxide synthase (iNOS;NOS2). The present study examined alveolar macrophages fixed directly after bronchopulmonary lavage. An average of 65% of the macrophages from 11 of 11 patients with untreated, culture-positive pulmonary tuberculosis reacted with an antibody documented herein to be monospecific for human NOS2. In contrast, a mean of 10% of bronchoalveolar lavage cells were positive from each of five clinically normal subjects. Tuberculosis patients' macrophages displayed diaphorase activity in the same proportion that they stained for NOS2, under assay conditions wherein the diaphorase reaction was strictly dependent on NOS2 expression. Bronchoalveolar lavage specimens also contained NOS2 mRNA. Thus, macrophages in the lungs of people with clinically active Mycobacterium tuberculosis infection often express catalytically competent NOS2.

Mechanism of the Nitric Oxide Dioxygenase Reaction of Mycobacterium tuberculosis Hemoglobin N

2017 ◽  
Vol 121 (37) ◽  
pp. 8706-8718 ◽  
Author(s):  
Lavinia A. Carabet ◽  
Michel Guertin ◽  
Patrick Lagüe ◽  
Guillaume Lamoureux
Keyword(s):  
Nitric Oxide ◽  
Mycobacterium Tuberculosis

scholarly journals Immunogenicity of Novel DosR Regulon-Encoded Candidate Antigens of Mycobacterium tuberculosis in Three High-Burden Populations in Africa

2009 ◽  
Vol 16 (8) ◽  
pp. 1203-1212 ◽  
Author(s):  
Gillian F. Black ◽  
Bonnie A. Thiel ◽  
Martin O. Ota ◽  
Shreemanta K. Parida ◽  
Richard Adegbola ◽  
...  
Keyword(s):  
South Africa ◽  
Mycobacterium Tuberculosis ◽  
South African ◽  
The Gambia ◽  
Human Populations ◽  
Protein Antigens ◽  
Immunodeficiency Virus ◽  
Study Participants ◽  
Dosr Regulon ◽  
Interferon Responses

ABSTRACT Increasing knowledge about DosR regulon-encoded proteins has led us to produce novel Mycobacterium tuberculosis antigens for immunogenicity testing in human populations in three countries in Africa to which tuberculosis (TB) is endemic. A total of 131 tuberculin skin test-positive and/or ESAT-6/CFP10-positive, human immunodeficiency virus-negative adult household contacts of active pulmonary TB cases from South Africa (n = 56), The Gambia (n = 26), and Uganda (n = 49) were tested for gamma interferon responses to 7 classical and 51 DosR regulon-encoded M. tuberculosis recombinant protein antigens. ESAT-6/CFP10 fusion protein evoked responses in >75% of study participants in all three countries. Of the DosR regulon-encoded antigens tested, Rv1733c was the most commonly recognized by participants from both South Africa and Uganda and the third most commonly recognized antigen in The Gambia. The four most frequently recognized DosR regulon-encoded antigens in Uganda (Rv1733c, Rv0081, Rv1735c, and Rv1737c) included the three most immunogenic antigens in South Africa. In contrast, Rv3131 induced the highest percentage of responders in Gambian contacts (38%), compared to only 3.4% of Ugandan contacts and no South African contacts. Appreciable percentages of TB contacts with a high likelihood of latent M. tuberculosis infection responded to several novel DosR regulon-encoded M. tuberculosis proteins. In addition to significant similarities in antigen recognition profiles between the three African population groups, there were also disparities, which may stem from genetic differences between both pathogen and host populations. Our findings have implications for the selection of potential TB vaccine candidates and for determining biosignatures of latent M. tuberculosis infection, active TB disease, and protective immunity.

scholarly journals Preclinical Evidence of Nanomedicine Formulation to Target Mycobacterium tuberculosis at Its Bone Marrow Niche

Pathogens ◽  
2020 ◽  
Vol 9 (5) ◽  
pp. 372 ◽  
Author(s):  
Jaishree Garhyan ◽  
Surender Mohan ◽  
Vinoth Rajendran ◽  
Rakesh Bhatnagar
Keyword(s):  
Bone Marrow ◽  
Mycobacterium Tuberculosis ◽  
In Vitro Release ◽  
Bone Marrow Niche ◽  
Mice Model ◽  
Latently Infected ◽  
Marrow Mesenchymal Stem Cells

One-third of the world’s population is estimated to be latently infected with Mycobacterium tuberculosis (Mtb). Recently, we found that dormant Mtb hides in bone marrow mesenchymal stem cells (BM-MSCs) post-chemotherapy in mice model and in clinical subjects. It is known that residual Mtb post-chemotherapy may be responsible for increased relapse rates. However, strategies for Mtb clearance post-chemotherapy are lacking. In this study, we engineered and formulated novel bone-homing PEGylated liposome nanoparticles (BTL-NPs) which actively targeted the bone microenvironment leading to Mtb clearance. Targeting of BM-resident Mtb was carried out through bone-homing liposomes tagged with alendronate (Ald). BTL characterization using TEM and DLS showed that the size of bone-homing isoniazid (INH) and rifampicin (RIF) BTLs were 100 ± 16.3 nm and 84 ± 18.4 nm, respectively, with the encapsulation efficiency of 69.5% ± 4.2% and 70.6% ± 4.7%. Further characterization of BTLs, displayed by sustained in vitro release patterns, increased in vivo tissue uptake and enhanced internalization of BTLs in RAW cells and CD271+BM-MSCs. The efficacy of isoniazid (INH)- and rifampicin (RIF)-loaded BTLs were shown using a mice model where the relapse rate of the tuberculosis was decreased significantly in targeted versus non-targeted groups. Our findings suggest that BTLs may play an important role in developing a clinical strategy for the clearance of dormant Mtb post-chemotherapy in BM cells.

scholarly journals Expression of the Nitric Oxide Synthase 2 Gene Is Not Essential for Early Control of Mycobacterium tuberculosis in the Murine Lung

2000 ◽  
Vol 68 (12) ◽  
pp. 6879-6882 ◽  
Author(s):  
Andrea M. Cooper ◽  
John E. Pearl ◽  
Jason V. Brooks ◽  
Stefan Ehlers ◽  
Ian M. Orme
Keyword(s):  
Nitric Oxide ◽  
Mycobacterium Tuberculosis ◽  
Nitric Oxide Synthase ◽  
Low Dose ◽  
Interleukin 12 ◽  
Infection Model ◽  
Rapid Progression ◽  
Ifn Γ ◽  
Nitric Oxide Synthase 2 ◽  
Oxide Synthase

ABSTRACT The interleukin-12 and gamma interferon (IFN-γ) pathway of macrophage activation plays a pivotal role in controlling tuberculosis. In the murine model, the generation of supplementary nitric oxide by the induction of the nitric oxide synthase 2 (NOS2) gene product is considered the principal antimicrobial mechanism of IFN-γ-activated macrophages. Using a low-dose aerosol-mediated infection model in the mouse, we have investigated the role of nitric oxide in controllingMycobacterium tuberculosis in the lung. In contrast to the consequences of a systemic infection, a low dose of bacteria introduced directly into the lungs of mice lacking the NOS2 gene is controlled almost as well as in intact animals. This is in contrast to the rapid progression of disease in mice lacking IFN-γ or a key member of the IFN signaling pathway, interferon regulatory factor 1. Thus while IFN-γ is pivotal in early control of bacterial growth in the lung, this control does not completely depend upon the expression of the NOS2 gene. The absence of inducible nitric oxide in the lung does, however, result in increased polymorphonuclear cell involvement and eventual necrosis in the pulmonary granulomas of the infected mice lacking the NOS2 gene.

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