Metabolic switching of Mycobacterium tuberculosis during hypoxia is controlled by the virulence regulator PhoP

Mapping Intimacies ◽

10.1101/845271 ◽

2019 ◽

Author(s):

Prabhat Ranjan Singh ◽

Vijjamarri Anil Kumar ◽

Dibyendu Sarkar

Keyword(s):

Mycobacterium Tuberculosis ◽

Nitrogen Metabolism ◽

Electron Acceptor ◽

Latent Infection ◽

Critical Role ◽

Hypoxic Stress ◽

Metabolic Switching ◽

Virulence Regulator ◽

Unique Ability

ABSTRACTMycobacterium tuberculosis (Mtb) retains the unique ability to establish an asymptomatic latent infection. A fundamental question in mycobacterial physiology is to understand the mechanisms involved in hypoxic stress, a critical player in persistence. Here, we show that the virulence regulator PhoP responds to hypoxia, the dormancy signal and effectively integrates hypoxia with nitrogen metabolism. We also provide evidence to demonstrate that both under nitrogen limiting conditions and during hypoxia, phoP locus controls key genes involved in nitrogen metabolism. Consistently, under hypoxia ΔphoP shows growth attenuation even with surplus nitrogen, the alternate electron acceptor, and complementation of the mutant restores bacterial growth. Together, our observations provide new biological insights into the role of PhoP in integrating nitrogen metabolism with hypoxia by the assistance of the hypoxia regulator DosR. The results have significant implications on the mechanism of intracellular survival and growth of the tubercle bacilli under a hypoxic environment within the phagosome.ImportanceMtb retains the unique ability to establish an asymptomatic latent infection. To understand the mechanisms involved in hypoxic stress which plays a critical role in persistence, we show that the virulence regulator PhoP responds to hypoxia, the dormancy signal. In keeping with this, phoP was shown to play a major role in Mtb growth under hypoxia even in presence of surplus nitrogen, the alternate electron acceptor. Our results showing regulation of hypoxia-responsive genes provide new biological insights into role of the virulence regulator in metabolic switching by sensing hypoxia and integrating nitrogen metabolism with hypoxia by the assistance of the hypoxia regulator DosR.

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Metabolic Switching of Mycobacterium tuberculosis during Hypoxia Is Controlled by the Virulence Regulator PhoP

Journal of Bacteriology ◽

10.1128/jb.00705-19 ◽

2020 ◽

Vol 202 (7) ◽

Author(s):

Prabhat Ranjan Singh ◽

Anil Kumar Vijjamarri ◽

Dibyendu Sarkar

Keyword(s):

Mycobacterium Tuberculosis ◽

Nitrogen Metabolism ◽

Electron Acceptor ◽

Latent Infection ◽

Critical Role ◽

Hypoxic Stress ◽

Content Type ◽

Metabolic Switching ◽

Virulence Regulator

ABSTRACT Mycobacterium tuberculosis retains the ability to establish an asymptomatic latent infection. A fundamental question in mycobacterial physiology is to understand the mechanisms involved in hypoxic stress, a critical player in persistence. Here, we show that the virulence regulator PhoP responds to hypoxia, the dormancy signal, and effectively integrates hypoxia with nitrogen metabolism. We also provide evidence to demonstrate that both under nitrogen limiting conditions and during hypoxia, phoP locus controls key genes involved in nitrogen metabolism. Consistently, under hypoxia a ΔphoP strain shows growth attenuation even with surplus nitrogen, the alternate electron acceptor, and complementation of the mutant restores bacterial growth. Together, our observations provide new biological insights into the role of PhoP in integrating nitrogen metabolism with hypoxia by the assistance of the hypoxia regulator DosR. The results have significant implications on the mechanism of intracellular survival and growth of the tubercle bacilli under a hypoxic environment within the phagosome. IMPORTANCE M. tuberculosis retains the unique ability to establish an asymptomatic latent infection. To understand the mechanisms involved in hypoxic stress which play a critical role in persistence, we show that the virulence regulator PhoP is linked to hypoxia, the dormancy signal. In keeping with this, phoP was shown to play a major role in M. tuberculosis growth under hypoxia even in the presence of surplus nitrogen, the alternate electron acceptor. Our results showing regulation of hypoxia-responsive genes provide new biological insights into role of the virulence regulator in metabolic switching by sensing hypoxia and integrating nitrogen metabolism with hypoxia by the assistance of the hypoxia regulator DosR.

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Critical role of amino acid position 343 of surfactant protein-D in the selective binding of glycolipids from Mycobacterium tuberculosis

Glycobiology ◽

10.1093/glycob/cwp122 ◽

2009 ◽

Vol 19 (12) ◽

pp. 1473-1484 ◽

Cited By ~ 15

Author(s):

Tracy K Carlson ◽

Jordi B Torrelles ◽

Kelly Smith ◽

Tim Horlacher ◽

Riccardo Castelli ◽

...

Keyword(s):

Mycobacterium Tuberculosis ◽

Amino Acid ◽

Critical Role ◽

Amino Acid Position ◽

Surfactant Protein ◽

Surfactant Protein D ◽

Selective Binding

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Th1 and Th17 Cells in Tuberculosis: Protection, Pathology, and Biomarkers

Mediators of Inflammation ◽

10.1155/2015/854507 ◽

2015 ◽

Vol 2015 ◽

pp. 1-13 ◽

Cited By ~ 85

Author(s):

I. V. Lyadova ◽

A. V. Panteleev

Keyword(s):

T Cells ◽

Th17 Cells ◽

Latent Infection ◽

Critical Role ◽

Active Tuberculosis ◽

Immune Reactivity ◽

Th1 Cells ◽

New Findings ◽

Pathogen Clearance

The outcome ofMycobacterium tuberculosis(Mtb) infection ranges from a complete pathogen clearance through asymptomatic latent infection (LTBI) to active tuberculosis (TB) disease. It is now understood that LTBI and active TB represent a continuous spectrum of states with different degrees of pathogen “activity,” host pathology, and immune reactivity. Therefore, it is important to differentiate LTBI and active TB and identify active TB stages. CD4+T cells play critical role duringMtbinfection by mediating protection, contributing to inflammation, and regulating immune response. Th1 and Th17 cells are the main effector CD4+T cells during TB. Th1 cells have been shown to contribute to TB protection by secreting IFN-γand activating antimycobacterial action in macrophages. Th17 induce neutrophilic inflammation, mediate tissue damage, and thus have been implicated in TB pathology. In recent years new findings have accumulated that alter our view on the role of Th1 and Th17 cells duringMtbinfection. This review discusses these new results and how they can be implemented for TB diagnosis and monitoring.

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Critical Role of a Single Position in the −35 Element for Promoter Recognition by Mycobacterium tuberculosis SigE and SigH

Journal of Bacteriology ◽

10.1128/jb.01642-07 ◽

2008 ◽

Vol 190 (6) ◽

pp. 2227-2230 ◽

Cited By ~ 32

Author(s):

Taeksun Song ◽

Seung-Eun Song ◽

Sahadevan Raman ◽

Mauricio Anaya ◽

Robert N. Husson

Keyword(s):

Mycobacterium Tuberculosis ◽

Critical Role ◽

Primer Extension ◽

Promoter Recognition

ABSTRACT Mycobacterial SigE and SigH both initiate transcription from the sigB promoter, suggesting that they recognize similar sequences. Through mutational and primer extension analyses, we determined that SigE and SigH recognize nearly identical promoters, with differences at the 3′ end of the −35 element distinguishing between SigE- and SigH-dependent promoters.

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New Aspects in Immunopathology of Mycobacterium tuberculosis

ISRN Immunology ◽

10.5402/2012/963879 ◽

2012 ◽

Vol 2012 ◽

pp. 1-11 ◽

Cited By ~ 2

Author(s):

E. Mortaz ◽

M. Varahram ◽

P. Farnia ◽

M. Bahadori ◽

MR Masjedi

Keyword(s):

Immune Response ◽

Innate Immunity ◽

Mycobacterium Tuberculosis ◽

Critical Role ◽

Etiologic Agent ◽

Innate Immune ◽

Major Health Problem ◽

Lectin Receptors ◽

Host Interactions

Our understanding of tuberculosis (TB) pathology and immunology has become extensively deeper and more refined since the identification of Mycobacterium tuberculosis (MTB) as the etiologic agent of disease by Dr. Robert Koch in 1882. A great challenge in chronic disease is to understand the complexities, mechanisms, and consequences of host interactions with pathogens. TB, caused by MTB, is a major health problem in world, with 10 million new cases diagnosed each year. Innate immunity is shown playing an important role in the host defense against the MTB, and the first step in this process is recognition of MTB by cells of the innate immune system. Several classes of pattern recognition receptors (PPRs) are involved in the recognition of MTB, including toll-like receptors (TLRs), C-type lectin receptors (CLRs), and nod-like receptors (NLRs). Among the TLR family, TLR1, TLR2, TLR4, and TLR9 and their down streams, proteins play the most prominent roles in the initiation of the immune response against MTB. Beside of TLRs signaling, recently the activation of inflammasome pathway in the pathogenesis of TB much appreciated. Knowledge about these signaling pathways is crucial for understanding the pathophysiology of TB, on one hand, and for the development of novel strategies of vaccination and treatment such as immunotherapy on the other. Given the critical role of TLRs/inflammasome signaling in innate immunity and initiation of the appropriate adaptive response, the regulation of these pathways is likely to be an important determinant of the clinical outcome of MTB infection. In this review paper we focused on the immune response, which is the recognition of MTB by inflammatory innate immune cells following infection.

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Critical role of AIM2 in Mycobacterium tuberculosis infection

International Immunology ◽

10.1093/intimm/dxs062 ◽

2012 ◽

Vol 24 (10) ◽

pp. 637-644 ◽

Cited By ~ 117

Author(s):

H. Saiga ◽

S. Kitada ◽

Y. Shimada ◽

N. Kamiyama ◽

M. Okuyama ◽

...

Keyword(s):

Mycobacterium Tuberculosis ◽

Critical Role ◽

Tuberculosis Infection ◽

Mycobacterium Tuberculosis Infection

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Ethambutol resistance in Mycobacterium tuberculosis: critical role of embB mutations.

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.41.8.1677 ◽

1997 ◽

Vol 41 (8) ◽

pp. 1677-1681 ◽

Cited By ~ 173

Author(s):

S Sreevatsan ◽

K E Stockbauer ◽

X Pan ◽

B N Kreiswirth ◽

S L Moghazeh ◽

...

Keyword(s):

Mycobacterium Tuberculosis ◽

Amino Acid ◽

Amino Acid Residue ◽

Critical Role ◽

Polymorphism Analysis ◽

Nucleotide Substitutions ◽

Automated Dna Sequencing ◽

Resistant Strains ◽

Conformation Polymorphism

Ethambutol [(S,S')-2,2'-(ethylenediimino)di-1-butanol; EMB], is a first-line drug used to treat tuberculosis. To gain insight into the molecular basis of EMB resistance, we characterized the 10-kb embCAB locus in 16 EMB-resistant and 3 EMB-susceptible genetically distinct Mycobacterium tuberculosis strains from diverse localities by automated DNA sequencing and single-stranded conformation polymorphism analysis. All 19 organisms had virtually identical sequences for the entire 10-kb region. Eight EMB-resistant organisms had mutations located in codon 306 of embB that resulted in the replacement of the wild-type Met residue with Ile or Val. Automated sequence analysis of the 5' region (1,892 bp) of embB in an additional 69 EMB-resistant and 30 EMB-susceptible M. tuberculosis isolates from diverse geographic localities and representing 70 distinct IS6110 fingerprints confirmed the unique association of substitutions in amino acid residue 306 of EmbB with EMB resistance. Six other embB nucleotide substitutions resulting in four amino acid replacements were uniquely found in resistant strains. Sixty-nine percent of epidemiologically unassociated EMB-resistant organisms had an amino acid substitution not found in susceptible strains, and most (89%) replacements occurred at amino acid residue 306 of EmbB. For strains with the Met306Leu or Met306Val replacements EMB MICs were generally higher (40 microg/ml) than those for organisms with Met306Ile substitutions (20 microg/ml). The data are consistent with the idea that amino acid substitutions in EmbB alter the drug-protein interaction and thereby cause EMB resistance.

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