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            , a Novel Carbon Monoxide Resistance Gene, Is Essential for Mycobacterium tuberculosis Pathogenesis

Zacharia, Vineetha M.; Manzanillo, Paolo; Nair, Vidhya R.; Marciano, Denise K.; Kinch, Lisa N.; Grishin, Nick V.; Cox, Jeffery S.; Shiloh, Michael U.

doi:10.1128/mbio.00721-13

Cited by 29 publications

(25 citation statements)

References 57 publications

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“…HO-1 derived CO has been shown to alter Mtb gene transcription and activate the mycobacterial dormancy regulon in experimental studies with mouse macrophages (27, 35). The recent identification of a gene mutation in Mtb strains that confers resistance to CO and leads to increased pathogenicity capacity in a murine TB model (36) suggests that CO resistance may be critical for Mtb survival and persistence in vivo . Our results demonstrating that CO strongly inhibits expression of MMP-1 argue that in addition to its antimicrobial effects, this metabolic product could have regulatory effects on collagen degradation in the lungs of TB patients.…”

Section: Discussionmentioning

confidence: 99%

Heme Oxygenase-1 Regulation of Matrix Metalloproteinase-1 Expression Underlies Distinct Disease Profiles in Tuberculosis

Andrade

Kumar

Amaral

et al. 2015

The Journal of Immunology

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Pulmonary tuberculosis (TB) is characterized by oxidative stress and lung tissue destruction by matrix metalloproteinases (MMP). The interplay between these distinct pathological processes and the implications for TB diagnosis and disease staging are poorly understood. Heme oxygenase-1 (HO-1) levels have been shown to distinguish active from latent as well as successfully treated Mycobacterium tuberculosis (Mtb) infection. MMP-1 expression is also associated with active TB. Here, we measured plasma levels of these two important biomarkers in distinct TB cohorts from India and Brazil. Patients with active TB expressed either very high levels of HO-1 and low levels of MMP-1 or the converse. Moreover, TB patients with either high HO-1 or MMP-1 levels displayed distinct clinical presentations as well as plasma inflammatory marker profiles. In contrast, in an exploratory North American study, inversely correlated expression of HO-1 and MMP-1 was not observed in patients with other non-tuberculous lung diseases. To assess possible regulatory interactions in the biosynthesis of these two enzymes at the cellular level, we studied expression of HO-1 and MMP-1 in Mtb-infected human and murine macrophages. We found that infection of macrophages with live virulent Mtb is required for robust induction of high levels of HO-1, but not MMP-1. In addition, we observed that carbon monoxide, a product of Mtb induced HO-1 activity, inhibits MMP-1 expression by suppressing c-Jun/AP-1 activation. These findings reveal a mechanistic link between oxidative stress and tissue remodeling that may find applicability in the clinical staging of TB patients.

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Section: Discussionmentioning

confidence: 99%

Heme Oxygenase-1 Regulation of Matrix Metalloproteinase-1 Expression Underlies Distinct Disease Profiles in Tuberculosis

Andrade

Kumar

Amaral

et al. 2015

The Journal of Immunology

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“…Plumbagin (10 l of 20 mM or 100 mM dissolved in ethanol), meropenem (10 g/ml or 20 g/ml dissolved in water), or clofazimine (10 g/ml dissolved in dimethyl sulfoxide) was added to separate sterile disks, which were placed on plates individually. The zone of growth inhibition was measured after 10 days of incubation, and each drug concentration was tested for each strain in triplicate (22).…”

Section: Methodsmentioning

confidence: 99%

Stringent Response Factors PPX1 and PPK2 Play an Important Role in Mycobacterium tuberculosis Metabolism, Biofilm Formation, and Sensitivity to Isoniazid In Vivo

Chuang

Dutta

Hung

et al. 2016

Antimicrob Agents Chemother

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g Mycobacterium tuberculosis remains a global health threat largely due to the lengthy duration of curative antibiotic treatment, contributing to medical nonadherence and the emergence of drug resistance. This prolonged therapy is likely due to the presence of M. tuberculosis persisters, which exhibit antibiotic tolerance. Inorganic polyphosphate [poly(P)] is a key regulatory molecule in the M. tuberculosis stringent response mediating antibiotic tolerance. The polyphosphate kinase PPK1 is responsible for poly(P) synthesis in M. tuberculosis, while the exopolyphosphatases PPX1 and PPX2 and the GTP synthase PPK2 are responsible for poly(P) hydrolysis. In the present study, we show by liquid chromatography-tandem mass spectrometry that poly(P)-accumulating M. tuberculosis mutant strains deficient in ppx1 or ppk2 had significantly lower intracellular levels of glycerol-3-phosphate (G3P) and 1-deoxy-xylulose-5-phosphate. Real-time PCR revealed decreased expression of genes in the G3P synthesis pathway in each mutant. The ppx1-deficient mutant also showed a significant accumulation of metabolites in the tricarboxylic acid cycle, as well as altered arginine and NADH metabolism. Each poly(P)-accumulating strain showed defective biofilm formation, while deficiency of ppk2 was associated with increased sensitivity to plumbagin and meropenem and deficiency of ppx1 led to enhanced susceptibility to clofazimine. A DNA vaccine expressing ppx1 and ppk2, together with two other members of the M. tuberculosis stringent response, M. tuberculosis rel and sigE, did not show protective activity against aerosol challenge with M. tuberculosis, but vaccine-induced immunity enhanced the killing activity of isoniazid in a murine model of chronic tuberculosis. In summary, poly(P)-regulating factors of the M. tuberculosis stringent response play an important role in M. tuberculosis metabolism, biofilm formation, and antibiotic sensitivity in vivo.

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“…BALBc mice (Jackson Laboratories) were infected using a Glas-Col aerosol-exposure chamber to deliver ~200 bacilli per mouse as previously described (19, 20). Prior to aerosolization, bacteria were washed repeatedly and sonicated to generate a single-cell suspension.…”

Section: Methodsmentioning

confidence: 99%

Heme Oxygenase-1 Regulates Inflammation and Mycobacterial Survival in Human Macrophages during Mycobacterium tuberculosis Infection

Scharn

Collins

Nair

et al. 2016

The Journal of Immunology

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Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis, is responsible for 1.5 million deaths annually. We previously showed that Mtb infection in mice induces expression of the carbon monoxide (CO) producing enzyme heme oxygenase (HO1) and that CO is sensed by Mtb to initiate a dormancy program. Further, mice deficient in HO1 succumb to Mtb infection more readily than wild type mice. While mouse macrophages control intracellular Mtb infection through several mechanisms such as nitric oxide synthase, the respiratory burst, acidification and autophagy, how human macrophages control Mtb infection remains less well understood. Here we show that Mtb induces and colocalizes with HO1 in both mouse and human tuberculosis lesions in vivo, and that Mtb induces and colocalizes with HO1 during primary human macrophage infection in vitro. Surprisingly, we find that chemical inhibition of HO1 both reduces inflammatory cytokine production by human macrophages and restricts intracellular growth of mycobacteria. Thus, induction of HO1 by Mtb infection may be a mycobacterial virulence mechanism to enhance inflammation and bacterial growth.

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cor , a Novel Carbon Monoxide Resistance Gene, Is Essential for Mycobacterium tuberculosis Pathogenesis

Cited by 29 publications

References 57 publications

Heme Oxygenase-1 Regulation of Matrix Metalloproteinase-1 Expression Underlies Distinct Disease Profiles in Tuberculosis

Heme Oxygenase-1 Regulation of Matrix Metalloproteinase-1 Expression Underlies Distinct Disease Profiles in Tuberculosis

Stringent Response Factors PPX1 and PPK2 Play an Important Role in Mycobacterium tuberculosis Metabolism, Biofilm Formation, and Sensitivity to Isoniazid In Vivo

Heme Oxygenase-1 Regulates Inflammation and Mycobacterial Survival in Human Macrophages during Mycobacterium tuberculosis Infection

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