The Role of Peroxisome Proliferator-Activated Receptor γ in Immune Responses to Enteroaggregative Escherichia coli Infection

Raffaella Bonecchi,Casandra W Philipson,Josep Bassaganya-Riera,Mireia Pedragosa,Monica Viladomiu,Richard L Guerrant,Raquel Hontecillas,James K Roche

doi:10.1371/journal.pone.0057812

Abstract

BackgroundEnteroaggregative 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 FindingsWild-type and T cell-specific PPARγ null C57BL/6 mice were fed protein-deficient diets at weaning and challenged with 5×109cfu 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.ConclusionsOur 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.

Highlights

Enteroaggregative E. coli (EAEC) is a Gram-negative, rodshaped bacterial pathogen of the Enterobacteriaceae family recognized as an emerging causative agent of gastroenteritis and diarrhea in developing and industrialized countries worldwide [1,2]
Our studies provide in vivo evidence supporting the beneficial role of mucosal innate and effector T cell responses on Enteroaggregative Escherichia coli (EAEC) burden and suggest pharmacological blockade of peroxisome proliferatoractivated receptor gamma (PPARc) as a novel therapeutic intervention for EAEC infection
PPARc null CD4cre+ mice on a control diet grew at rates similar to uninfected mice while nourished infected wild type (WT) mice experienced significant retardation in growth up to 11 days after challenge (Figure 1A–B)

Summary

Introduction

Enteroaggregative E. coli (EAEC) is a Gram-negative, rodshaped bacterial pathogen of the Enterobacteriaceae family recognized as an emerging causative agent of gastroenteritis and diarrhea in developing and industrialized countries worldwide [1,2]. Malnutrition predisposes individuals to infection by impairing epithelial barrier integrity and suppressing immune responses [7]. Adverse effects to intestinal absorption are exacerbated during infection generating a catabolic state that depletes nutrients needed for tissue synthesis and growth further increasing the likelihood of pathogens breaching the epithelial barrier [8]. EAEC infections hinder the functionality of the epithelial barrier disrupting nutrient absorption worsening malnutrition and potentiating growth retardation [10]. Enteroaggregative Escherichia coli (EAEC) is recognized as an emerging cause of persistent diarrhea and enteric disease worldwide. This study presents a new mouse model and investigates the role of peroxisome proliferatoractivated receptor gamma (PPARc) in the modulation of host responses to EAEC in nourished and malnourished mice

Methods

Results

Conclusion