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Calprotectin Increases the Activity of the SaeRS Two Component System and Murine Mortality during Staphylococcus aureus Infections.

Cho H, Jeong DW, Liu Q, Yeo WS, Vogl T, Skaar EP, Chazin WJ, Bae T - PLoS Pathog. (2015)

Bottom Line: Here we show that calprotectin can also enhance the activity of the SaeRS two component system (TCS), a signaling system essential for production of over 20 virulence factors in S. aureus.During staphylococcal encounter with murine neutrophils or staphylococcal infection of the murine peritoneal cavity, calprotectin increases the activity of the SaeRS TCS as well as the production of proinflammatory cytokines such as IL-1β and TNF-α, resulting in higher murine mortality.These results suggest that, under certain conditions, calprotectin can be exploited by S. aureus to increase bacterial virulence and host mortality.

View Article: PubMed Central - PubMed

Affiliation: Indiana University School of Medicine-Northwest, Gary, Indiana, United States of America.

ABSTRACT
Calprotectin, the most abundant cytoplasmic protein in neutrophils, suppresses the growth of Staphylococcus aureus by sequestering the nutrient metal ions Zn and Mn. Here we show that calprotectin can also enhance the activity of the SaeRS two component system (TCS), a signaling system essential for production of over 20 virulence factors in S. aureus. The activity of the SaeRS TCS is repressed by certain divalent ions found in blood or neutrophil granules; however, the Zn bound-form of calprotectin relieves this repression. During staphylococcal encounter with murine neutrophils or staphylococcal infection of the murine peritoneal cavity, calprotectin increases the activity of the SaeRS TCS as well as the production of proinflammatory cytokines such as IL-1β and TNF-α, resulting in higher murine mortality. These results suggest that, under certain conditions, calprotectin can be exploited by S. aureus to increase bacterial virulence and host mortality.

No MeSH data available.


Related in: MedlinePlus

RNA-seq analysis of the effect of CP, Zn and Zn-CP on staphylococcal transcriptome.S. aureus USA300 cells at exponential growth phase were treated by CP (1.1 μM), Zn (20 μM) or Zn (20 μM)-CP (1.1 μM) at 37°C for 4 h; then the transcript levels were analyzed by RNA-seq. (A) The number of genes affected by CP, Zn, and Zn-CP. (B) Venn diagram analysis of the genes affected by CP, Zn, and Zn-CP. Up, up-regulated genes; Down, down-regulated genes. (C) Effect of CP, Zn, and Zn-CP on the transcript levels of the sae regulon. -, no treatment. ID, Gene ID in the genome of the strain USA300_FPR3757.
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ppat.1005026.g004: RNA-seq analysis of the effect of CP, Zn and Zn-CP on staphylococcal transcriptome.S. aureus USA300 cells at exponential growth phase were treated by CP (1.1 μM), Zn (20 μM) or Zn (20 μM)-CP (1.1 μM) at 37°C for 4 h; then the transcript levels were analyzed by RNA-seq. (A) The number of genes affected by CP, Zn, and Zn-CP. (B) Venn diagram analysis of the genes affected by CP, Zn, and Zn-CP. Up, up-regulated genes; Down, down-regulated genes. (C) Effect of CP, Zn, and Zn-CP on the transcript levels of the sae regulon. -, no treatment. ID, Gene ID in the genome of the strain USA300_FPR3757.

Mentions: To understand the effect of CP and Zn on staphylococcal gene expression, we treated the strain USA300 at its exponential growth phase with CP, Zn, or Zn-CP and assessed the transcriptome changes at 4 h post treatment by RNA-seq analysis. The CP treatment altered the transcript level of 221 genes (Fig 4A, S1 and S2 Tables), indicating that the effect of CP is global and not limited to the SaeRS TCS. The Zn and Zn-CP treatments induced profound changes in the staphylococcal gene expression affecting 949 and 871 genes, respectively (Fig 4A, S3–S6 Tables). The Zn and Zn-CP treatments shared 396 (up-regulated) and 305 (down-regulated) genes (Fig 2B), indicating that, when Zn and CP were added together, Zn exerts a dominant effect on the staphylococcal transcription. The dominant effect of Zn over CP is also corroborated by the principal component analysis (S2 Fig). Nonetheless, the addition of CP to Zn also elicited up-regulation of 45 genes and down-regulation of 133 genes, which was not observed in the Zn-treated cells (Fig 4B). When only the sae regulon was analyzed, CP up-regulated 7 genes, while Zn down-regulated 28 genes (Fig 4C), confirming the positive and negative effects of CP and Zn on the SaeRS TCS. When treated with Zn-CP, overall, the sae regulon remained repressed, as compared with control medium condition (Fig 4C). However, as compared with Zn treatment, all genes showed a higher level of transcripts to disparate extents. In particular, two genes, SAUSA300_1055 and 1757, showed transcript levels similar to that in the control medium (Fig 4C). When compared with Zn treatment, the Zn-CP treatment significantly up-regulated 14 genes and down-regulated 43 genes (S7 and S8 Tables). Of the 14 up-regulated genes, 10 contain the SaeR binding sequence in their promoter region (S7 Table), indicating that, although the CP induces global changes in staphylococcal gene expression, the protective effect in the presence of Zn is rather specific to the SaeRS TCS.


Calprotectin Increases the Activity of the SaeRS Two Component System and Murine Mortality during Staphylococcus aureus Infections.

Cho H, Jeong DW, Liu Q, Yeo WS, Vogl T, Skaar EP, Chazin WJ, Bae T - PLoS Pathog. (2015)

RNA-seq analysis of the effect of CP, Zn and Zn-CP on staphylococcal transcriptome.S. aureus USA300 cells at exponential growth phase were treated by CP (1.1 μM), Zn (20 μM) or Zn (20 μM)-CP (1.1 μM) at 37°C for 4 h; then the transcript levels were analyzed by RNA-seq. (A) The number of genes affected by CP, Zn, and Zn-CP. (B) Venn diagram analysis of the genes affected by CP, Zn, and Zn-CP. Up, up-regulated genes; Down, down-regulated genes. (C) Effect of CP, Zn, and Zn-CP on the transcript levels of the sae regulon. -, no treatment. ID, Gene ID in the genome of the strain USA300_FPR3757.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4492782&req=5

ppat.1005026.g004: RNA-seq analysis of the effect of CP, Zn and Zn-CP on staphylococcal transcriptome.S. aureus USA300 cells at exponential growth phase were treated by CP (1.1 μM), Zn (20 μM) or Zn (20 μM)-CP (1.1 μM) at 37°C for 4 h; then the transcript levels were analyzed by RNA-seq. (A) The number of genes affected by CP, Zn, and Zn-CP. (B) Venn diagram analysis of the genes affected by CP, Zn, and Zn-CP. Up, up-regulated genes; Down, down-regulated genes. (C) Effect of CP, Zn, and Zn-CP on the transcript levels of the sae regulon. -, no treatment. ID, Gene ID in the genome of the strain USA300_FPR3757.
Mentions: To understand the effect of CP and Zn on staphylococcal gene expression, we treated the strain USA300 at its exponential growth phase with CP, Zn, or Zn-CP and assessed the transcriptome changes at 4 h post treatment by RNA-seq analysis. The CP treatment altered the transcript level of 221 genes (Fig 4A, S1 and S2 Tables), indicating that the effect of CP is global and not limited to the SaeRS TCS. The Zn and Zn-CP treatments induced profound changes in the staphylococcal gene expression affecting 949 and 871 genes, respectively (Fig 4A, S3–S6 Tables). The Zn and Zn-CP treatments shared 396 (up-regulated) and 305 (down-regulated) genes (Fig 2B), indicating that, when Zn and CP were added together, Zn exerts a dominant effect on the staphylococcal transcription. The dominant effect of Zn over CP is also corroborated by the principal component analysis (S2 Fig). Nonetheless, the addition of CP to Zn also elicited up-regulation of 45 genes and down-regulation of 133 genes, which was not observed in the Zn-treated cells (Fig 4B). When only the sae regulon was analyzed, CP up-regulated 7 genes, while Zn down-regulated 28 genes (Fig 4C), confirming the positive and negative effects of CP and Zn on the SaeRS TCS. When treated with Zn-CP, overall, the sae regulon remained repressed, as compared with control medium condition (Fig 4C). However, as compared with Zn treatment, all genes showed a higher level of transcripts to disparate extents. In particular, two genes, SAUSA300_1055 and 1757, showed transcript levels similar to that in the control medium (Fig 4C). When compared with Zn treatment, the Zn-CP treatment significantly up-regulated 14 genes and down-regulated 43 genes (S7 and S8 Tables). Of the 14 up-regulated genes, 10 contain the SaeR binding sequence in their promoter region (S7 Table), indicating that, although the CP induces global changes in staphylococcal gene expression, the protective effect in the presence of Zn is rather specific to the SaeRS TCS.

Bottom Line: Here we show that calprotectin can also enhance the activity of the SaeRS two component system (TCS), a signaling system essential for production of over 20 virulence factors in S. aureus.During staphylococcal encounter with murine neutrophils or staphylococcal infection of the murine peritoneal cavity, calprotectin increases the activity of the SaeRS TCS as well as the production of proinflammatory cytokines such as IL-1β and TNF-α, resulting in higher murine mortality.These results suggest that, under certain conditions, calprotectin can be exploited by S. aureus to increase bacterial virulence and host mortality.

View Article: PubMed Central - PubMed

Affiliation: Indiana University School of Medicine-Northwest, Gary, Indiana, United States of America.

ABSTRACT
Calprotectin, the most abundant cytoplasmic protein in neutrophils, suppresses the growth of Staphylococcus aureus by sequestering the nutrient metal ions Zn and Mn. Here we show that calprotectin can also enhance the activity of the SaeRS two component system (TCS), a signaling system essential for production of over 20 virulence factors in S. aureus. The activity of the SaeRS TCS is repressed by certain divalent ions found in blood or neutrophil granules; however, the Zn bound-form of calprotectin relieves this repression. During staphylococcal encounter with murine neutrophils or staphylococcal infection of the murine peritoneal cavity, calprotectin increases the activity of the SaeRS TCS as well as the production of proinflammatory cytokines such as IL-1β and TNF-α, resulting in higher murine mortality. These results suggest that, under certain conditions, calprotectin can be exploited by S. aureus to increase bacterial virulence and host mortality.

No MeSH data available.


Related in: MedlinePlus