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

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.

Animal models of enteroaggregativeEscherichia coliinfection

“…Asterisks (*) indicate statistical significance compared with uninfected mice and the number symbol (#) represents statistical difference compared with infected wild type mice (p < 0.05). 81 Modulating the parameters regulating T cell differentiation into separate phenotypes simulated PPARγ deficiency: Th1 and Th17 cell differentiation was enhanced equally while Treg differentiation was decreased in an equal magnitude. Bacterial clearance predicted in silico mimicked EAEC quantification in feces from infected mice (B).…”

“…73 Recently, our group published in vivo data reporting for the first time the importance of T helper (Th)17 cells in host responses to EAEC and EAEC clearance. 81 By pharmacologically and genetically disrupting the activity of the transcription factor peroxisome proliferator-activated receptor (PPAR) γ in malnourished mice, we modulated mucosal inflammation that resulted in enhanced Th17 phenotypes and disease amelioration ( fig. 1, first and fifth enterocytes, underlying mucosa).…”

IL-17A promotes protective IgA responses and expression of other potential effectors against the lumen-dwelling enteric parasite Giardia

“…The cytokine can have both protective and pathogenic effects in different infection and inflammation models and organ systems (Onishi and Gaffen, 2010). In the intestinal tract, IL-17A is required for protective immunity against Helicobacter pylori (Algood, et al, 2009), Citrobacter rodentium (Ishigame, et al, 2009), Salmonella enterica serovar Typhimurium (Mayuzumi, et al, 2010; Raffatellu, et al, 2008), and enteroaggregative Escherichia coli (Philipson, et al, 2013), indicating that IL-17A is an important regulator of mucosal immune defenses associated with mucosal inflammation. Although Giardia infection is typically devoid of acute inflammatory events (Oberhuber, et al, 1997), a recent study found that IL-17A contributes to clearance of the murine pathogen Giardia muris (Dreesen, et al, 2014).…”

Enteroaggregative Escherichia coli: A Pathogen Bridging the North and South

“…The EAEC 042 genome was characterized in 2010, it is comprised by a circular chromosome of 5,241,977 bp and one plasmid of 113,346bp, known as the “aggregative adherence plasmid” (pAA)[12]. The other EAEC reference strain that has been used in animal models is JMM221, which has been particularly useful for understanding the EAEC immune response in malnourished mice [13]. …”