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

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.

背景
肠集聚性大肠埃希菌（Enteroaggregative Escherichia coli, EAEC）已被认定为全球范围内持续性腹泻与肠道疾病的新兴致病菌。由于缺乏合适的动物模型，目前针对EAEC感染的黏膜免疫机制尚未完全阐明。本研究构建了一种新型小鼠模型，旨在探究过氧化物酶体增殖物激活受体γ（peroxisome proliferator-activated receptor gamma, PPARγ）在营养充足与营养不良小鼠体内，对宿主针对EAEC的免疫应答的调控作用。

方法与主要结果
将野生型及T细胞特异性PPARγ敲除C57BL/6小鼠在断奶后喂食低蛋白饲料，并以5×10^9菌落形成单位的EAEC菌株JM221进行攻毒，以此检测结肠基因表达水平与宿主针对EAEC的免疫应答。研究检测了感染后营养充足与营养不良小鼠针对大肠埃希菌抗原的特异性免疫应答，从细胞层面证实了营养不良的免疫抑制效应。在分子层面，T细胞中PPARγ的药物阻断与基因敲除均可导致转化生长因子-β（TGF-β）、白细胞介素-6（IL-6）、白细胞介素-17（IL-17）及抗菌肽的表达上调，增强Th17细胞应答，减少结肠病理损伤，加速EAEC清除并改善小鼠康复状态。体内中和IL-17可抵消PPARγ阻断对小鼠体重减轻及EAEC清除的有益作用。

结论
本研究提供了体内实验证据，证实黏膜固有免疫与效应T细胞应答可降低EAEC载量，并提出PPARγ的药物阻断可作为EAEC感染的新型治疗干预手段。