Mycobacterium tuberculosis Senses Host-Derived Carbon Monoxide during Macrophage Infection

Shiloh, Michael U.; Manzanillo, Paolo; Cox, Jeffery S.

doi:10.1016/j.chom.2008.03.007

Cited by 198 publications

(235 citation statements)

References 66 publications

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“…Additionally, we observed a significant increase in HO-1 expression in both murine macrophage RAW264.7 and hepatoma Hepa1-6 cells (unpublished data). This is consistent with previously published studies demonstrating an upregulation of HO-1 mRNA and/or protein expression in response to bacterial (29,(40)(41)(42)(43)(44)(45) or parasitic (26,27,46) infections and might be a general response of infected host cells.…”

Section: Discussionsupporting

confidence: 82%

Heme Oxygenase-1 and Carbon Monoxide PromoteBurkholderia pseudomalleiInfection

Stolt

Schmidt

Sayfart

et al. 2016

The Journal of Immunology

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The environmental bacterium and potential biothreat agent Burkholderia pseudomallei causes melioidosis, an often fatal infectious disease. Increased serum bilirubin has been shown to be a negative predictive factor in melioidosis patients. We therefore investigated the role of heme oxygenase-1 (HO-1), which catalyzes the degradation of heme into the bilirubin precursor biliverdin, ferrous iron, and CO during B. pseudomallei infection. We found that infection of murine macrophages induces HO-1 expression, involving activation of several protein kinases and the transcription factor nuclear erythroid-related factor 2 (Nrf2). Deficiency of Nrf2 improved B. pseudomallei clearance by macrophages, whereas Nrf2 activation by sulforaphane and tert-butylhydroquinone with subsequent HO-1 induction enhanced intracellular bacterial growth. The HO-1 inducer cobalt protoporphyrin IX diminished proinflammatory cytokine levels, leading to an increased bacterial burden in macrophages. In contrast, HO-1 gene knockdown reduced the survival of intramacrophage B. pseudomallei. Pharmacological administration of cobalt protoporphyrin IX to mice resulted in an enhanced bacterial load in various organs and was associated with higher mortality of intranasally infected mice. The unfavorable outcome of B. pseudomallei infection after HO-1 induction was associated with higher serum IL-6, TNF-α, and MCP-1 levels but decreased secretion of IFN-γ. Finally, we demonstrate that the CO-releasing molecule CORM-2 increases the B. pseudomallei load in macrophages and mice. Thus, our data suggest that the B. pseudomallei–mediated induction of HO-1 and the release of its metabolite CO impair bacterial clearance in macrophages and during murine melioidosis.

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Section: Discussionsupporting

confidence: 82%

Heme Oxygenase-1 and Carbon Monoxide PromoteBurkholderia pseudomalleiInfection

Stolt

Schmidt

Sayfart

et al. 2016

The Journal of Immunology

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“…2): (1) divalent gas: when stimulated by hypoxia [Park et al, 2003;Sherman et al, 2001], nitric oxide [Sherman et al, 2001], and carbon monoxide [Kumar et al, 2008;Shiloh et al, 2008], the expression level of DosR regulon is upregulated, followed by the oxygen consumption shifting, ATP levels maintenance and redox state (NAD/NADH ratio) homeostasis. Its expression level is also vital to the optimal transition of Mtb from the anaerobic nonreplicating state back to aerobic growth state .…”

Section: The Expression and Regulation Of Dosr Regulonmentioning

confidence: 99%

The Mycobacterium DosR regulon structure and diversity revealed by comparative genomic analysis

Chen

Deng

et al. 2012

J of Cellular Biochemistry

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Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), which claims approximately two million people annually, remains a global health concern. The non-replicating or dormancy like state of this pathogen which is impervious to anti-tuberculosis drugs is widely recognized as the culprit for this scenario. The dormancy survival regulator (DosR) regulon, composed of 48 co-regulated genes, is held as essential for Mtb persistence. The DosR regulon is regulated by a two-component regulatory system consisting of two sensor kinases-DosS (Rv3132c) and DosT (Rv2027c), and a response regulator DosR (Rv3133c). The underlying regulatory mechanism of DosR regulon expression is very complex. Many factors are involved, particularly the oxygen tension. The DosR regulon enables the pathogen to persist during lengthy hypoxia. Comparative genomic analysis demonstrated that the DosR regulon is widely distributed among the mycobacterial genomes, ranging from the pathogenic strains to the environmental strains. In-depth studies on the DosR response should provide insights into its role in TB latency in vivo and shape new measures to combat this exceeding recalcitrant pathogen.

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“…Activation of DosR induces a dormant state in the bacterium, allowing it to survive successfully within macrophages. DosS and DosT play roles in the recognition of hypoxic conditions as redox and oxygen sensors, respectively, and are structurally very similar to one another (8,9). The architecture of these HKs can be divided into an N-terminal sensor core and a C-terminal kinase core (KC) (see Fig.…”

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confidence: 99%