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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: 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.

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

The proinflammatory property of CP increases murine mortality.(A) Effect of CP on the survival of mice infected by S. aureus. C57BL/6 (WT) or C57BL/6 S100A9-/- (A9-/-) mice were infected with USA300 (USA) or sae-deletion mutant (Δsae) by intraperitoneal injection (2×108 cfu). Ten mice were used for each test group. Statistical significance was assessed by Log-rank (Mantel-Cox) test. (B) Effect of individual proinflammatory cytokine antibodies on the murine survival. WT or A9-/- mice were infected with the wild type USA300 (2 × 108 cfu). At 2 h post infection, 100 μg of the indicated antibody was injected via i.p. route. (C) Effect of proinflammatory cytokine antibody mixture on the murine survival. WT or A9-/- mice were infected with the wild type USA300 (2 × 108 cfu). At 2 h post infection, 150 μg of proinflammatory cytokine antibody (50 μg of each IFN-γ Ab, TNF-α Ab, and IL-1β Ab) was injected via i.p. route. (D) CP can increase murine mortality in the absence of the SaeRS TCS. WT or A9-/- mice were infected with the sae-deletion mutant (Δsae, 1 × 109 cfu). Statistical significance was assessed by Log-rank (Mantel-Cox) test. ns, not significant; **, p < 0.01; ***, p < 0.001
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ppat.1005026.g007: The proinflammatory property of CP increases murine mortality.(A) Effect of CP on the survival of mice infected by S. aureus. C57BL/6 (WT) or C57BL/6 S100A9-/- (A9-/-) mice were infected with USA300 (USA) or sae-deletion mutant (Δsae) by intraperitoneal injection (2×108 cfu). Ten mice were used for each test group. Statistical significance was assessed by Log-rank (Mantel-Cox) test. (B) Effect of individual proinflammatory cytokine antibodies on the murine survival. WT or A9-/- mice were infected with the wild type USA300 (2 × 108 cfu). At 2 h post infection, 100 μg of the indicated antibody was injected via i.p. route. (C) Effect of proinflammatory cytokine antibody mixture on the murine survival. WT or A9-/- mice were infected with the wild type USA300 (2 × 108 cfu). At 2 h post infection, 150 μg of proinflammatory cytokine antibody (50 μg of each IFN-γ Ab, TNF-α Ab, and IL-1β Ab) was injected via i.p. route. (D) CP can increase murine mortality in the absence of the SaeRS TCS. WT or A9-/- mice were infected with the sae-deletion mutant (Δsae, 1 × 109 cfu). Statistical significance was assessed by Log-rank (Mantel-Cox) test. ns, not significant; **, p < 0.01; ***, p < 0.001

Mentions: Since CP enhanced the activity of the SaeRS TCS and the production of several proinflammatory cytokines, both of which can be detrimental to the survival of the host, next we examined the effect of CP on the mortality of the infected mice. When infected with wild type USA300, all wild type mice died by 14 h post infection, whereas 70% of CP-deficient mice were alive (Fig 7A). At 24 h post infection, 20% of CP-deficient mice were still alive. These results suggest that indeed CP is detrimental for murine survival during staphylococcal peritoneal infection. On the other hand, when infected with the Δsae mutant, no mice died, regardless of the genetic background (Fig 7A), demonstrating the importance of the SaeRS TCS in the bacterial virulence. To test whether the detrimental effect of CP on host survival depends on infection route, we administered S. aureus cells into mice via retro-orbital injection. When infected with wild type USA300, only 10% of wild type mice survived by day 14, whereas yet 60% of CP-deficient mice were still alive (S6 Fig). When infected by Δsae mutant, all mice survived again (S6 Fig). This observation demonstrates that the increased mortality of wild type mice infected with S. aureus USA300 is dependent on CP but independent of the infection routes.


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)

The proinflammatory property of CP increases murine mortality.(A) Effect of CP on the survival of mice infected by S. aureus. C57BL/6 (WT) or C57BL/6 S100A9-/- (A9-/-) mice were infected with USA300 (USA) or sae-deletion mutant (Δsae) by intraperitoneal injection (2×108 cfu). Ten mice were used for each test group. Statistical significance was assessed by Log-rank (Mantel-Cox) test. (B) Effect of individual proinflammatory cytokine antibodies on the murine survival. WT or A9-/- mice were infected with the wild type USA300 (2 × 108 cfu). At 2 h post infection, 100 μg of the indicated antibody was injected via i.p. route. (C) Effect of proinflammatory cytokine antibody mixture on the murine survival. WT or A9-/- mice were infected with the wild type USA300 (2 × 108 cfu). At 2 h post infection, 150 μg of proinflammatory cytokine antibody (50 μg of each IFN-γ Ab, TNF-α Ab, and IL-1β Ab) was injected via i.p. route. (D) CP can increase murine mortality in the absence of the SaeRS TCS. WT or A9-/- mice were infected with the sae-deletion mutant (Δsae, 1 × 109 cfu). Statistical significance was assessed by Log-rank (Mantel-Cox) test. ns, not significant; **, p < 0.01; ***, p < 0.001
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4492782&req=5

ppat.1005026.g007: The proinflammatory property of CP increases murine mortality.(A) Effect of CP on the survival of mice infected by S. aureus. C57BL/6 (WT) or C57BL/6 S100A9-/- (A9-/-) mice were infected with USA300 (USA) or sae-deletion mutant (Δsae) by intraperitoneal injection (2×108 cfu). Ten mice were used for each test group. Statistical significance was assessed by Log-rank (Mantel-Cox) test. (B) Effect of individual proinflammatory cytokine antibodies on the murine survival. WT or A9-/- mice were infected with the wild type USA300 (2 × 108 cfu). At 2 h post infection, 100 μg of the indicated antibody was injected via i.p. route. (C) Effect of proinflammatory cytokine antibody mixture on the murine survival. WT or A9-/- mice were infected with the wild type USA300 (2 × 108 cfu). At 2 h post infection, 150 μg of proinflammatory cytokine antibody (50 μg of each IFN-γ Ab, TNF-α Ab, and IL-1β Ab) was injected via i.p. route. (D) CP can increase murine mortality in the absence of the SaeRS TCS. WT or A9-/- mice were infected with the sae-deletion mutant (Δsae, 1 × 109 cfu). Statistical significance was assessed by Log-rank (Mantel-Cox) test. ns, not significant; **, p < 0.01; ***, p < 0.001
Mentions: Since CP enhanced the activity of the SaeRS TCS and the production of several proinflammatory cytokines, both of which can be detrimental to the survival of the host, next we examined the effect of CP on the mortality of the infected mice. When infected with wild type USA300, all wild type mice died by 14 h post infection, whereas 70% of CP-deficient mice were alive (Fig 7A). At 24 h post infection, 20% of CP-deficient mice were still alive. These results suggest that indeed CP is detrimental for murine survival during staphylococcal peritoneal infection. On the other hand, when infected with the Δsae mutant, no mice died, regardless of the genetic background (Fig 7A), demonstrating the importance of the SaeRS TCS in the bacterial virulence. To test whether the detrimental effect of CP on host survival depends on infection route, we administered S. aureus cells into mice via retro-orbital injection. When infected with wild type USA300, only 10% of wild type mice survived by day 14, whereas yet 60% of CP-deficient mice were still alive (S6 Fig). When infected by Δsae mutant, all mice survived again (S6 Fig). This observation demonstrates that the increased mortality of wild type mice infected with S. aureus USA300 is dependent on CP but independent of the infection routes.

Bottom Line: 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.

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