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The SaeR/S gene regulatory system induces a pro-inflammatory cytokine response during Staphylococcus aureus infection.

Watkins RL, Pallister KB, Voyich JM - PLoS ONE (2011)

Bottom Line: In contrast, mice infected with an isogenic saeR/S deletion mutant demonstrated significantly reduced pro-inflammatory cytokine levels.Additionally, secreted factors influenced by saeR/S elicited pro-inflammatory cytokines in human blood ex vivo.Results also indicated a critical role for saeR/S in promoting bacterial survival and enhancing host mortality during S. aureus peritonitis.

View Article: PubMed Central - PubMed

Affiliation: Department of Immunology/Infectious Diseases, Montana State University-Bozeman, Bozeman, Montana, United States of America.

ABSTRACT
Community-associated methicillin-resistant Staphylococcus aureus accounts for a large portion of the increased staphylococcal disease incidence and can cause illness ranging from mild skin infections to rapidly fatal sepsis syndromes. Currently, we have limited understanding of S. aureus-derived mechanisms contributing to bacterial pathogenesis and host inflammation during staphylococcal disease. Herein, we characterize an influential role for the saeR/S two-component gene regulatory system in mediating cytokine induction using mouse models of S. aureus pathogenesis. Invasive S. aureus infection induced the production of localized and systemic pro-inflammatory cytokines, including tumor necrosis factor alpha (TNF-α), interferon gamma (IFN-γ), interleukin (IL)-6 and IL-2. In contrast, mice infected with an isogenic saeR/S deletion mutant demonstrated significantly reduced pro-inflammatory cytokine levels. Additionally, secreted factors influenced by saeR/S elicited pro-inflammatory cytokines in human blood ex vivo. Our study further demonstrated robust saeR/S-mediated IFN-γ production during both invasive and subcutaneous skin infections. Results also indicated a critical role for saeR/S in promoting bacterial survival and enhancing host mortality during S. aureus peritonitis. Taken together, this study provides insight into specific mechanisms used by S. aureus during staphylococcal disease and characterizes a relationship between a bacterial global regulator of virulence and the production of pro-inflammatory mediators.

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SaeR/S elicits systemic pro-inflammatory cytokines during invasive S. aureus infection.Mice were inoculated i.p. with MW2, MW2ΔsaeR/S (5×107 cfu) or PBS for 10 hours and serum cytokine concentrations were measured by cytometric bead array. Serum concentrations (pg/ml) of (A) IFN-γ, (B) TNF, (C) IL-6, (D) IL-2, (E) IL-17A, (F) IL-10 and (G) IL-4. Results displayed are from 5 mice (MW2), 7 mice (MW2ΔsaeR/S) and 2 mice (PBS). *P<0.05 and **P<0.01 compared to cytokine expression in MW2-infected mice for each cytokine investigated as determined by t test. NS = not significant; N/D = not detectable.
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pone-0019939-g002: SaeR/S elicits systemic pro-inflammatory cytokines during invasive S. aureus infection.Mice were inoculated i.p. with MW2, MW2ΔsaeR/S (5×107 cfu) or PBS for 10 hours and serum cytokine concentrations were measured by cytometric bead array. Serum concentrations (pg/ml) of (A) IFN-γ, (B) TNF, (C) IL-6, (D) IL-2, (E) IL-17A, (F) IL-10 and (G) IL-4. Results displayed are from 5 mice (MW2), 7 mice (MW2ΔsaeR/S) and 2 mice (PBS). *P<0.05 and **P<0.01 compared to cytokine expression in MW2-infected mice for each cytokine investigated as determined by t test. NS = not significant; N/D = not detectable.

Mentions: Sepsis and septic shock are associated with the systemic production of inflammatory cytokines [11]–[14]. To determine if the saeR/S-mediated inflammatory response was systemic during S. aureus peritonitis, we infected mice i.p. with 5×107 cfu of MW2 or MW2ΔsaeR/S for 10 hours and measured protein levels of several pro- and anti-inflammatory cytokines in the serum by cytometric bead array (figure 2). Of note, serum IFN-γand TNF levels were significantly reduced in mice infected with MW2ΔsaeR/S (P<0.05 and P<0.01, respectively; figures 2A and 2B). Additional pro-inflammatory cytokines associated with sepsis syndromes were influenced by saeR/S as serum IL-6 and IL-2 concentrations were significantly lower in MW2ΔsaeR/S-infected mice (P<0.01; figure 2C and 2D). Serum IL-17A levels were also significantly reduced in mice infected with MW2ΔsaeR/S (P<0.01; figure 2E). In contrast, IL-4 and IL-10 serum concentrations did not exhibit differences between MW2 and MW2ΔsaeR/S-infected groups (P>0.05; figures 2F and 2G). These results are consistent with previous sepsis syndrome observations, in which an early pro-inflammatory cytokine response (IFN-γ, TNF, IL-2, and IL-6) was concomitant with a relatively subdued anti-inflammatory cytokine (IL-4 and IL-10) response [13], [14]. The differentially regulated transcriptional activity in the peritoneum (Tables 1 and S1) and the polarized pro-inflammatory cytokine response in the blood (figure 2) indicate that saeR/S-regulated factors promote localized and systemic inflammation during invasive disease.


The SaeR/S gene regulatory system induces a pro-inflammatory cytokine response during Staphylococcus aureus infection.

Watkins RL, Pallister KB, Voyich JM - PLoS ONE (2011)

SaeR/S elicits systemic pro-inflammatory cytokines during invasive S. aureus infection.Mice were inoculated i.p. with MW2, MW2ΔsaeR/S (5×107 cfu) or PBS for 10 hours and serum cytokine concentrations were measured by cytometric bead array. Serum concentrations (pg/ml) of (A) IFN-γ, (B) TNF, (C) IL-6, (D) IL-2, (E) IL-17A, (F) IL-10 and (G) IL-4. Results displayed are from 5 mice (MW2), 7 mice (MW2ΔsaeR/S) and 2 mice (PBS). *P<0.05 and **P<0.01 compared to cytokine expression in MW2-infected mice for each cytokine investigated as determined by t test. NS = not significant; N/D = not detectable.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3094403&req=5

pone-0019939-g002: SaeR/S elicits systemic pro-inflammatory cytokines during invasive S. aureus infection.Mice were inoculated i.p. with MW2, MW2ΔsaeR/S (5×107 cfu) or PBS for 10 hours and serum cytokine concentrations were measured by cytometric bead array. Serum concentrations (pg/ml) of (A) IFN-γ, (B) TNF, (C) IL-6, (D) IL-2, (E) IL-17A, (F) IL-10 and (G) IL-4. Results displayed are from 5 mice (MW2), 7 mice (MW2ΔsaeR/S) and 2 mice (PBS). *P<0.05 and **P<0.01 compared to cytokine expression in MW2-infected mice for each cytokine investigated as determined by t test. NS = not significant; N/D = not detectable.
Mentions: Sepsis and septic shock are associated with the systemic production of inflammatory cytokines [11]–[14]. To determine if the saeR/S-mediated inflammatory response was systemic during S. aureus peritonitis, we infected mice i.p. with 5×107 cfu of MW2 or MW2ΔsaeR/S for 10 hours and measured protein levels of several pro- and anti-inflammatory cytokines in the serum by cytometric bead array (figure 2). Of note, serum IFN-γand TNF levels were significantly reduced in mice infected with MW2ΔsaeR/S (P<0.05 and P<0.01, respectively; figures 2A and 2B). Additional pro-inflammatory cytokines associated with sepsis syndromes were influenced by saeR/S as serum IL-6 and IL-2 concentrations were significantly lower in MW2ΔsaeR/S-infected mice (P<0.01; figure 2C and 2D). Serum IL-17A levels were also significantly reduced in mice infected with MW2ΔsaeR/S (P<0.01; figure 2E). In contrast, IL-4 and IL-10 serum concentrations did not exhibit differences between MW2 and MW2ΔsaeR/S-infected groups (P>0.05; figures 2F and 2G). These results are consistent with previous sepsis syndrome observations, in which an early pro-inflammatory cytokine response (IFN-γ, TNF, IL-2, and IL-6) was concomitant with a relatively subdued anti-inflammatory cytokine (IL-4 and IL-10) response [13], [14]. The differentially regulated transcriptional activity in the peritoneum (Tables 1 and S1) and the polarized pro-inflammatory cytokine response in the blood (figure 2) indicate that saeR/S-regulated factors promote localized and systemic inflammation during invasive disease.

Bottom Line: In contrast, mice infected with an isogenic saeR/S deletion mutant demonstrated significantly reduced pro-inflammatory cytokine levels.Additionally, secreted factors influenced by saeR/S elicited pro-inflammatory cytokines in human blood ex vivo.Results also indicated a critical role for saeR/S in promoting bacterial survival and enhancing host mortality during S. aureus peritonitis.

View Article: PubMed Central - PubMed

Affiliation: Department of Immunology/Infectious Diseases, Montana State University-Bozeman, Bozeman, Montana, United States of America.

ABSTRACT
Community-associated methicillin-resistant Staphylococcus aureus accounts for a large portion of the increased staphylococcal disease incidence and can cause illness ranging from mild skin infections to rapidly fatal sepsis syndromes. Currently, we have limited understanding of S. aureus-derived mechanisms contributing to bacterial pathogenesis and host inflammation during staphylococcal disease. Herein, we characterize an influential role for the saeR/S two-component gene regulatory system in mediating cytokine induction using mouse models of S. aureus pathogenesis. Invasive S. aureus infection induced the production of localized and systemic pro-inflammatory cytokines, including tumor necrosis factor alpha (TNF-α), interferon gamma (IFN-γ), interleukin (IL)-6 and IL-2. In contrast, mice infected with an isogenic saeR/S deletion mutant demonstrated significantly reduced pro-inflammatory cytokine levels. Additionally, secreted factors influenced by saeR/S elicited pro-inflammatory cytokines in human blood ex vivo. Our study further demonstrated robust saeR/S-mediated IFN-γ production during both invasive and subcutaneous skin infections. Results also indicated a critical role for saeR/S in promoting bacterial survival and enhancing host mortality during S. aureus peritonitis. Taken together, this study provides insight into specific mechanisms used by S. aureus during staphylococcal disease and characterizes a relationship between a bacterial global regulator of virulence and the production of pro-inflammatory mediators.

Show MeSH
Related in: MedlinePlus