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The role of peroxisome proliferator-activated receptor γ in immune responses to enteroaggregative Escherichia coli infection.

Philipson CW, Bassaganya-Riera J, Viladomiu M, Pedragosa M, Guerrant RL, Roche JK, Hontecillas R - PLoS ONE (2013)

Bottom Line: At the molecular level, both pharmacological blockade and deletion of PPARγ in T cells resulted in upregulation of TGF-β, IL-6, IL-17 and anti-microbial peptides, enhanced Th17 responses, fewer colonic lesions, faster clearance of EAEC, and improved recovery.The beneficial effects of PPARγ blockade on weight loss and EAEC clearance were abrogated by neutralizing IL-17 in vivo.Our studies provide in vivo evidence supporting the beneficial role of mucosal innate and effector T cell responses on EAEC burden and suggest pharmacological blockade of PPARγ as a novel therapeutic intervention for EAEC infection.

View Article: PubMed Central - PubMed

Affiliation: Nutritional Immunology and Molecular Medicine Laboratory, Virginia Bioinformatics Institute, Virginia Tech, Blacksburg, Virginia, United States of America.

ABSTRACT

Background: Enteroaggregative Escherichia coli (EAEC) is recognized as an emerging cause of persistent diarrhea and enteric disease worldwide. Mucosal immunity towards EAEC infections is incompletely understood due in part to the lack of appropriate animal models. This study presents a new mouse model and investigates the role of peroxisome proliferator-activated receptor gamma (PPARγ) in the modulation of host responses to EAEC in nourished and malnourished mice.

Methods/principal findings: Wild-type and T cell-specific PPARγ C57BL/6 mice were fed protein-deficient diets at weaning and challenged with 5×10(9)cfu EAEC strain JM221 to measure colonic gene expression and immune responses to EAEC. Antigen-specific responses to E. coli antigens were measured in nourished and malnourished mice following infection and demonstrated the immunosuppressive effects of malnutrition at the cellular level. At the molecular level, both pharmacological blockade and deletion of PPARγ in T cells resulted in upregulation of TGF-β, IL-6, IL-17 and anti-microbial peptides, enhanced Th17 responses, fewer colonic lesions, faster clearance of EAEC, and improved recovery. The beneficial effects of PPARγ blockade on weight loss and EAEC clearance were abrogated by neutralizing IL-17 in vivo.

Conclusions: Our studies provide in vivo evidence supporting the beneficial role of mucosal innate and effector T cell responses on EAEC burden and suggest pharmacological blockade of PPARγ as a novel therapeutic intervention for EAEC infection.

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Related in: MedlinePlus

Neutralization of IL-17 abrogates the beneficial effects of GW9662 on weight loss and bacterial burden.Growth retardation in infected wild type mice is expressed as percent growth from day 0 after challenge (A). Enteroaggregative Escherichia coli (EAEC) burden in the colon was assessed by quantitative real time RT-PCR using bacterial DNA isolated from feces of infected mice treated with 1 µM PPARγ antagonist GW9662 (n = 3), 50 µg anti-IL17 and 1 µM GW9662 combined (n = 3) or untreated (n = 3). Asterisks indicate values where differences are statistically significant (p<0.05), NS signifies no significant difference, and bars are present to indicate significance between groups.
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pone-0057812-g005: Neutralization of IL-17 abrogates the beneficial effects of GW9662 on weight loss and bacterial burden.Growth retardation in infected wild type mice is expressed as percent growth from day 0 after challenge (A). Enteroaggregative Escherichia coli (EAEC) burden in the colon was assessed by quantitative real time RT-PCR using bacterial DNA isolated from feces of infected mice treated with 1 µM PPARγ antagonist GW9662 (n = 3), 50 µg anti-IL17 and 1 µM GW9662 combined (n = 3) or untreated (n = 3). Asterisks indicate values where differences are statistically significant (p<0.05), NS signifies no significant difference, and bars are present to indicate significance between groups.

Mentions: Simultaneous treatment with anti-IL17A and GW9662 (1 µM) resulted in significant differences in body weight beginning on day 3 post-infection (Figure 5A). The pattern of weight loss in mice treated with both anti-IL17A and GW9662 resembled that of untreated mice. Mice solely receiving GW9662 grew at significantly faster rates than the other two groups beginning 3 days after infection. More importantly, significant weight loss coincided with increased bacterial burdens on day 3 PI in mice from non-treated and anti-IL17A+GW9662 groups when compared to GW9662 treatment alone (Figure 5B). These data suggest that the beneficial effects on the host resulting from PPARγ blockade are largely mediated by IL-17A. An additional study performed to assess dose-response effects of GW9662 on IL-17 production revealed that increasing concentrations of GW9662 during infection significantly upregulated colonic IL-17A mRNA expression (Figure S4).


The role of peroxisome proliferator-activated receptor γ in immune responses to enteroaggregative Escherichia coli infection.

Philipson CW, Bassaganya-Riera J, Viladomiu M, Pedragosa M, Guerrant RL, Roche JK, Hontecillas R - PLoS ONE (2013)

Neutralization of IL-17 abrogates the beneficial effects of GW9662 on weight loss and bacterial burden.Growth retardation in infected wild type mice is expressed as percent growth from day 0 after challenge (A). Enteroaggregative Escherichia coli (EAEC) burden in the colon was assessed by quantitative real time RT-PCR using bacterial DNA isolated from feces of infected mice treated with 1 µM PPARγ antagonist GW9662 (n = 3), 50 µg anti-IL17 and 1 µM GW9662 combined (n = 3) or untreated (n = 3). Asterisks indicate values where differences are statistically significant (p<0.05), NS signifies no significant difference, and bars are present to indicate significance between groups.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3585146&req=5

pone-0057812-g005: Neutralization of IL-17 abrogates the beneficial effects of GW9662 on weight loss and bacterial burden.Growth retardation in infected wild type mice is expressed as percent growth from day 0 after challenge (A). Enteroaggregative Escherichia coli (EAEC) burden in the colon was assessed by quantitative real time RT-PCR using bacterial DNA isolated from feces of infected mice treated with 1 µM PPARγ antagonist GW9662 (n = 3), 50 µg anti-IL17 and 1 µM GW9662 combined (n = 3) or untreated (n = 3). Asterisks indicate values where differences are statistically significant (p<0.05), NS signifies no significant difference, and bars are present to indicate significance between groups.
Mentions: Simultaneous treatment with anti-IL17A and GW9662 (1 µM) resulted in significant differences in body weight beginning on day 3 post-infection (Figure 5A). The pattern of weight loss in mice treated with both anti-IL17A and GW9662 resembled that of untreated mice. Mice solely receiving GW9662 grew at significantly faster rates than the other two groups beginning 3 days after infection. More importantly, significant weight loss coincided with increased bacterial burdens on day 3 PI in mice from non-treated and anti-IL17A+GW9662 groups when compared to GW9662 treatment alone (Figure 5B). These data suggest that the beneficial effects on the host resulting from PPARγ blockade are largely mediated by IL-17A. An additional study performed to assess dose-response effects of GW9662 on IL-17 production revealed that increasing concentrations of GW9662 during infection significantly upregulated colonic IL-17A mRNA expression (Figure S4).

Bottom Line: At the molecular level, both pharmacological blockade and deletion of PPARγ in T cells resulted in upregulation of TGF-β, IL-6, IL-17 and anti-microbial peptides, enhanced Th17 responses, fewer colonic lesions, faster clearance of EAEC, and improved recovery.The beneficial effects of PPARγ blockade on weight loss and EAEC clearance were abrogated by neutralizing IL-17 in vivo.Our studies provide in vivo evidence supporting the beneficial role of mucosal innate and effector T cell responses on EAEC burden and suggest pharmacological blockade of PPARγ as a novel therapeutic intervention for EAEC infection.

View Article: PubMed Central - PubMed

Affiliation: Nutritional Immunology and Molecular Medicine Laboratory, Virginia Bioinformatics Institute, Virginia Tech, Blacksburg, Virginia, United States of America.

ABSTRACT

Background: Enteroaggregative Escherichia coli (EAEC) is recognized as an emerging cause of persistent diarrhea and enteric disease worldwide. Mucosal immunity towards EAEC infections is incompletely understood due in part to the lack of appropriate animal models. This study presents a new mouse model and investigates the role of peroxisome proliferator-activated receptor gamma (PPARγ) in the modulation of host responses to EAEC in nourished and malnourished mice.

Methods/principal findings: Wild-type and T cell-specific PPARγ C57BL/6 mice were fed protein-deficient diets at weaning and challenged with 5×10(9)cfu EAEC strain JM221 to measure colonic gene expression and immune responses to EAEC. Antigen-specific responses to E. coli antigens were measured in nourished and malnourished mice following infection and demonstrated the immunosuppressive effects of malnutrition at the cellular level. At the molecular level, both pharmacological blockade and deletion of PPARγ in T cells resulted in upregulation of TGF-β, IL-6, IL-17 and anti-microbial peptides, enhanced Th17 responses, fewer colonic lesions, faster clearance of EAEC, and improved recovery. The beneficial effects of PPARγ blockade on weight loss and EAEC clearance were abrogated by neutralizing IL-17 in vivo.

Conclusions: Our studies provide in vivo evidence supporting the beneficial role of mucosal innate and effector T cell responses on EAEC burden and suggest pharmacological blockade of PPARγ as a novel therapeutic intervention for EAEC infection.

Show MeSH
Related in: MedlinePlus