Bedi Brahmchetna, Maurice Nicholas M, Ciavatta Vincent T, Lynn K Sabrina, Yuan Zhihong, Molina Samuel A, Joo Myungsoo, Tyor William R, Goldberg Joanna B, Koval Michael, Hart C Michael, Sadikot Ruxana T
Atlanta Veterans Affairs Medical Center, Decatur, Georgia, USA.
Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, Emory University, Atlanta, Georgia, USA.
FASEB J. 2017 Aug;31(8):3608-3621. doi: 10.1096/fj.201700075R. Epub 2017 Apr 25.
is a significant contributor to recalcitrant multidrug-resistant infections, especially in immunocompromised and hospitalized patients. The pathogenic profile of is related to its ability to secrete a variety of virulence factors and to promote biofilm formation. Quorum sensing (QS) is a mechanism wherein secretes small diffusible molecules, specifically acyl homo serine lactones, such as N-(3-oxo-dodecanoyl)--homoserine lactone (3O-C12-HSL), that promote biofilm formation and virulence interbacterial communication. Strategies that strengthen the host's ability to inhibit bacterial virulence would enhance host defenses and improve the treatment of resistant infections. We have recently shown that peroxisome proliferator-activated receptor γ (PPARγ) agonists are potent immunostimulators that play a pivotal role in host response to virulent Here, we show that QS genes in (strain PAO1) and 3O-C12-HSL attenuate PPARγ expression in bronchial epithelial cells. PAO1 and 3O-C12-HSL induce barrier derangements in bronchial epithelial cells by lowering the expression of junctional proteins, such as zonula occludens-1, occludin, and claudin-4. Expression of these proteins was restored in cells that were treated with pioglitazone, a PPARγ agonist, before infection with PAO1 and 3O-C12-HSL. Barrier function and bacterial permeation studies that have been performed in primary human epithelial cells showed that PPARγ agonists are able to restore barrier integrity and function that are disrupted by PAO1 and 3O-C12-HSL. Mechanistically, we show that these effects are dependent on the induction of paraoxonase-2, a QS hydrolyzing enzyme, that mitigates the effects of QS molecules. Importantly, our data show that pioglitazone, a PPARγ agonist, significantly inhibits biofilm formation on epithelial cells by a mechanism that is mediated paraoxonase-2. These findings elucidate a novel role for PPARγ in host defense against Strategies that activate PPARγ can provide a therapeutic complement for treatment of resistant infections.-Bedi, B., Maurice, N. M., Ciavatta, V. T., Lynn, K. S., Yuan, Z., Molina, S. A., Joo, M., Tyor, W. R., Goldberg, J. B., Koval, M., Hart, C. M., Sadikot, R. T. Peroxisome proliferator-activated receptor-γ agonists attenuate biofilm formation by .
是顽固性多重耐药感染的重要促成因素，尤其是在免疫功能低下和住院患者中。其致病特征与其分泌多种毒力因子和促进生物膜形成的能力有关。群体感应（QS）是一种机制，其中会分泌可扩散的小分子，特别是酰基高丝氨酸内酯，如N-（3-氧代十二烷酰基）-L-高丝氨酸内酯（3O-C12-HSL），可促进生物膜形成和毒力以及细菌间通讯。增强宿主抑制细菌毒力能力的策略将增强宿主防御并改善耐药感染的治疗。我们最近表明，过氧化物酶体增殖物激活受体γ（PPARγ）激动剂是有效的免疫刺激剂，在宿主对毒力的反应中起关键作用。在此，我们表明铜绿假单胞菌（菌株PAO1）中的QS基因和3O-C12-HSL会减弱支气管上皮细胞中PPARγ的表达。PAO1和3O-C12-HSL通过降低紧密连接蛋白（如闭合蛋白-1、闭合蛋白和Claudin-4）的表达，诱导支气管上皮细胞中的屏障紊乱。在用PPARγ激动剂吡格列酮处理过的细胞中，在感染PAO1和3O-C12-HSL之前，这些蛋白的表达得以恢复。在原代人上皮细胞中进行的屏障功能和细菌渗透研究表明，PPARγ激动剂能够恢复被PAO1和3O-C12-HSL破坏的屏障完整性和功能。从机制上讲，我们表明这些作用取决于对对氧磷酶-2（一种QS水解酶）的诱导，该酶可减轻QS分子的作用。重要的是，我们的数据表明，PPARγ激动剂吡格列酮通过一种由对氧磷酶-2介导的机制，显著抑制上皮细胞上的生物膜形成。这些发现阐明了PPARγ在宿主抵御铜绿假单胞菌中的新作用。激活PPARγ的策略可为耐药铜绿假单胞菌感染的治疗提供一种治疗补充。-贝迪，B.，莫里斯，N.M.，恰瓦塔，V.T.，林恩，K.S.，袁，Z.，莫利纳，S.A.，朱，M.，蒂奥尔，W.R.，戈德堡，J.B.，科瓦尔，M.，哈特，C.M.，萨迪科特，R.T.过氧化物酶体增殖物激活受体-γ激动剂减弱铜绿假单胞菌的生物膜形成
