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Impact of glutamine transporters on pneumococcal fitness under infection-related conditions.

ABSTRACT: The genomic analysis of Streptococcus pneumoniae predicted six putative glutamine uptake systems, which are expressed under in vitro conditions, as shown here by reverse transcription-PCR. Four of these operons consist of glnHPQ, while two lack glnH, which encodes a soluble glutamine-binding protein. Here, we studied the impact of two of these glutamine ATP-binding cassette transporters on S. pneumoniae D39 virulence and phagocytosis, which consist of GlnQ and a translationally fused protein of GlnH and GlnP. Mice infected intranasally with D39?gln0411/0412 showed significantly increased survival times and a significant delay in the development of pneumococcal pneumonia compared to those infected with D39, as observed in real time using bioluminescent pneumococci. In a mouse sepsis model, the mutant D39?gln0411/0412 showed only moderate but significant attenuation. In contrast, the D39?gln1098/1099 knockout strain was massively attenuated in the pneumonia and septicemia mouse infection model. To cause pneumonia or sepsis with D39?gln1098/1099, infection doses 100- to 10,000-fold higher than those used for wild-type strain D39 were required. In an experimental mouse meningitis model, D39?gln1098/1099 produced decreased levels of white blood cells in cerebrospinal fluid and showed decreased numbers of bacteria in the bloodstream compared to D39 and D39?gln0411/0412. Phagocytosis experiments revealed significantly decreased intracellular survival rates of mutants D39?gln1098/1099 and D39?gln0411/0412 compared to wild-type D39, suggesting that the deficiency of Gln uptake systems impairs resistance to oxidative stress. Taken together, our results demonstrate that both glutamine uptake systems are required for full virulence of pneumococci but exhibit different impacts on the pathogenesis of pneumococci under in vivo conditions.

SUBMITTER: Hartel T

PROVIDER: S-EPMC3019899 | biostudies-other | 2011 Jan

REPOSITORIES: biostudies-other

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Impact of glutamine transporters on pneumococcal fitness under infection-related conditions.

Härtel Tobias T Klein Matthias M Koedel Uwe U Rohde Manfred M Petruschka Lothar L Hammerschmidt Sven S

Infection and immunity 20101115 1

The genomic analysis of Streptococcus pneumoniae predicted six putative glutamine uptake systems, which are expressed under in vitro conditions, as shown here by reverse transcription-PCR. Four of these operons consist of glnHPQ, while two lack glnH, which encodes a soluble glutamine-binding protein. Here, we studied the impact of two of these glutamine ATP-binding cassette transporters on S. pneumoniae D39 virulence and phagocytosis, which consist of GlnQ and a translationally fused protein of ...[more]

PMID: 21078855

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Project description:Among gynecologic malignancies, ovarian cancer is the third most prevalent and the most common cause of death, especially due to diagnosis at an advanced stage together with resistance to therapy. As a solid tumor grows, cancer cells in the microenvironment are exposed to regions of hypoxia, a selective pressure prompting tumor progression and chemoresistance. We have previously shown that cysteine contributes to the adaptation to this hypoxic microenvironment, but the mechanisms by which cysteine protects ovarian cancer cells from hypoxia-induced death are still to be unveiled. Herein, we hypothesized that cysteine contribution relies on cellular metabolism reprogramming and energy production, being cysteine itself a metabolic source. Our results strongly supported a role of xCT symporter in energy production that requires cysteine metabolism instead of hydrogen sulfide (H2S) per se. Cysteine degradation depends on the action of the H2S-synthesizing enzymes cystathionine β-synthase (CBS), cystathionine γ-lyase (CSE), and/or 3-mercaptopyruvate sulfurtransferase (MpST; together with cysteine aminotransferase, CAT). In normoxia, CBS and CSE inhibition had a mild impact on cysteine-sustained ATP production, pointing out the relevance of CAT + MpST pathway. However, in hypoxia, the concomitant inhibition of CBS and CSE had a stronger impact on ATP synthesis, thus also supporting a role of their hydrogen sulfide and/or cysteine persulfide-synthesizing activity in this stressful condition. However, the relative contributions of each of these enzymes (CBS/CSE/MpST) on cysteine-derived ATP synthesis under hypoxia remains unclear, due to the lack of specific inhibitors. Strikingly, NMR analysis strongly supported a role of cysteine in the whole cellular metabolism rewiring under hypoxia. Additionally, the use of cysteine to supply biosynthesis and bioenergetics was reinforced, bringing cysteine to the plateau of a main carbon sources in cancer. Collectively, this work supports that sulfur and carbon metabolism reprogramming underlies the adaptation to hypoxic microenvironment promoted by cysteine in ovarian cancer.

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Impact of glutamine transporters on pneumococcal fitness under infection-related conditions.

Publications

Impact of glutamine transporters on pneumococcal fitness under infection-related conditions.

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