CtpV: a putative copper exporter required for full virulence of Mycobacterium tuberculosis

Ward, Sarah K.; Abomoelak, Bassam; Hoye, Elizabeth A.; Steinberg, Howard; Talaat, Adel M.

doi:10.1111/j.1365-2958.2010.07273.x

Cited by 171 publications

(232 citation statements)

References 43 publications

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“…However, previous studies showed only a modest increase in Cu susceptibility of Mtb in the absence of the copper-binding metallothionein MymT (12) and the putative inner membrane CtpV (11) and no or only a minor virulence defect in mice or guinea pigs. By contrast, the survival of the ΔmctB mutant ML256 in the lungs of guinea pigs was strongly impaired as compared with WT Mtb, resulting in a 1,000-and 100-fold reduced bacterial burden in lungs and lymph nodes (Fig.…”

Section: Discussionmentioning

confidence: 83%

“…The ctpV gene (rv0969) is part of a Cu-induced operon controlled by the transcriptional regulator CsoR (10) and likely encodes a Cu-specific inner membrane efflux pump (9,10). However, the ctpV mutant did not show a clear virulence defect in mice and guinea pigs (11). Further, Mtb produces the metallothionine MymT, a small protein that binds up to six Cu(I) ions and partially protects Mtb from Cu toxicity (12).…”

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confidence: 99%

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Copper resistance is essential for virulence of Mycobacterium tuberculosis

Wolschendorf

Ackart

Shrestha

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

287

333

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Copper (Cu) is essential for many biological processes, but is toxic when present in excessive amounts. In this study, we provide evidence that Cu plays a crucial role in controlling tuberculosis. A Mycobacterium tuberculosis ( Mtb ) mutant lacking the outer membrane channel protein Rv1698 accumulated 100-fold more Cu and was more susceptible to Cu toxicity than WT Mtb . Similar phenotypes were observed for a M. smegmatis mutant lacking the homolog Ms3747, demonstrating that these mycobacterial copper transport proteins B (MctB) are essential for Cu resistance and maintenance of low intracellular Cu levels. Guinea pigs responded to infection with Mtb by increasing the Cu concentration in lung lesions. Loss of MctB resulted in a 1,000- and 100-fold reduced bacterial burden in lungs and lymph nodes, respectively, in guinea pigs infected with Mtb . In mice, the persistence defect of the Mtb mctB mutant was exacerbated by the addition of Cu to the diet. These experiments provide evidence that Cu is used by the mammalian host to control Mtb infection and that Cu resistance mechanisms are crucial for Mtb virulence. Importantly, Mtb is much more susceptible to Cu than other bacteria and is killed in vitro by Cu concentrations lower than those found in phagosomes of macrophages. Hence, this study reveals an Achilles heel of Mtb that might be a promising target for tuberculosis chemotherapy.

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Section: Discussionmentioning

confidence: 83%

mentioning

confidence: 99%

Copper resistance is essential for virulence of Mycobacterium tuberculosis

Wolschendorf

Ackart

Shrestha

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

287

333

View full text Add to dashboard Cite

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“…The gene ctpV, encoding an exporter, is induced during infection of macrophages (Graham & Clark-Curtiss, 1999) and in the Wayne hypoxia model (Muttucumaru et al, 2004) and is required for copper efflux as well as for detoxification and full virulence of Mtb during copper stress (Ward et al, 2010). Studies have suggested that copper homeostasis mechanisms may play a role in the outcome of bacterial infections (Ward et al, 2010). Like ctpV, ctpG is also copper inducible (Rowland & Niederweis, 2012), but it is predicted to function in the efflux of zinc (Argüello et al, 2007).…”

Section: Transportmentioning

confidence: 99%

The pleiotropic transcriptional response of Mycobacterium tuberculosis to vitamin C is robust and overlaps with the bacterial response to multiple intracellular stresses

et al. 2015

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Mycobacterium tuberculosis (Mtb) owes its success as a pathogen in large measure to its ability to exist in a persistent state of 'dormancy' resulting in a lifelong latent tuberculosis (TB) infection. An understanding of bacterial adaptation during dormancy will help in devising approaches to counter latent TB infection. In vitro models have provided valuable insights into bacterial adaptation; however, they have limitations because they do not disclose the bacterial response to the intracellular environment wherein the bacteria are simultaneously exposed to multiple stresses. We describe the pleiotropic response of Mtb in the vitamin C (vit C) model of dormancy developed in our laboratory. Vit C mediates a rapid regulation of genes representing~14 % of the genome in Mtb cultures. The upregulated genes were better represented in lipid, intermediary metabolism and regulatory protein categories. The downregulated genes mainly related to virulence, detoxification, information pathways and cell wall processes. A comparison of this response to that in other models indicates that vit C generates a multiple-stress environment for axenic Mtb cultures that resembles a macrophage-like environment. The bacterial response to vit C resembles responses to gaseous stresses such as hypoxia and nitric oxide, oxidative and nitrosative stresses, nutrient starvation and, notably, the activated macrophage environment itself. These responses demonstrate that the influence of vit C on Mtb gene expression extends well beyond the DevR dormancy regulon. A detailed characterization of the response to vit C is expected to disclose useful strategies to counter the adaptive mechanisms essential to Mtb dormancy.

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“…Transcription of this operon is induced by copper, consistent with the predicted role of CtpV in excretion of excess copper under free-living conditions. Additionally, expression of ctpV is induced during infection of mouse lungs, suggesting a role of the copper-ATPase in virulence (Ward et al, 2010).…”

Section: Myc Tuberculosismentioning

confidence: 99%