Identification of Specific Components of the Eicosanoid Biosynthetic and Signaling Pathway Involved in Pathological Inflammation during Intra-abdominal Infection with Candida albicans and Staphylococcus aureus.
Identification of Specific Components of the Eicosanoid Biosynthetic and Signaling Pathway Involved in Pathological Inflammation during Intra-abdominal Infection with Candida albicans and Staphylococcus aureus.
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白色念珠菌和金黄色葡萄球菌腹内感染期间参与病理炎症的类二十烷酸生物合成和信号通路的特定成分的鉴定。
DOI：
10.1128/iai.00144-18
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发表时间：
2018
影响因子：
3.1
通讯作者：
Noverr,MairiC
中科院分区：
文献类型：
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作者：
Ikeh,MélanieAC;FidelJr,PaulL;Noverr,MairiC
多菌腹内感染是发病率和死亡率的重要原因，尤其是在涉及真菌病原体的情况下。我们的实验性小鼠腹膜腔内接种白色念珠菌和金黄色葡萄球菌，由于炎症加剧，导致协同致死率(∼80%)。单一微生物感染不会导致死亡，尽管微生物的负担和传播类似于混合感染。在混合感染模型中，免疫调节的二十烷类前列腺素E2(PGE2)被认为是诱导死亡的必要条件和充分条件，这意味着PGE2是放大的炎症反应的中心介质。本研究的目的是确定参与炎症反应的PGE2生物合成和信号通路的关键成分，并探索这些关键成分是否可以作为预防或降低死亡率的靶点。在白色念珠菌中使用选择性环氧合酶(COX)抑制剂或PGE2受体拮抗剂。在金黄色葡萄球菌IAI小鼠模型中，我们发现抑制COX和/或阻断PGE2受体1(EP1)或PGE2受体3(EP3)信号会减少促炎细胞因子的产生，促进白细胞介素10的产生，减少腹膜腔内的细胞损伤，最重要的是显著提高存活率。同时抑制COX-1活性和EP1、EP3受体信号转导对存活率的影响最大。重要的是，与单独使用氟康唑相比，早期抑制PGE2通路显著提高了氟康唑治疗的小鼠的存活率。这些结果表明，COX-1、EP1和EP3受体介导了PGE2在多菌IAI过程中的下游病理效应，可能成为有效的治疗靶点。
Polymicrobial intra-abdominal infections (IAIs) are a significant cause of morbidity and mortality, particularly when fungal pathogens are involved. Our experimental murine model of IAI involving intraperitoneal inoculation of Candida albicans and Staphylococcus aureus results in synergistic lethality (∼80%) due to exacerbated inflammation. Monomicrobial infection results in no mortality, despite a microbial burden and dissemination similar to those in a coinfection. In the coinfection model, the immunomodulatory eicosanoid prostaglandin E2(PGE2) was determined to be necessary and sufficient to induce mortality, implicating PGE2as the central mediator of the amplified inflammatory response. The aim of this study was to identify key components of the PGE2biosynthetic and signaling pathway involved in the inflammatory response and explore whether these can be targeted to prevent or reduce mortality. Using selective pharmacological inhibitors of cyclooxygenases (COX) or PGE2receptor antagonists in the C. albicans-S. aureus IAI mouse model, we found that inhibition of COX and/or blocking of PGE2receptor 1 (EP1) or PGE2receptor 3 (EP3) signaling reduced proinflammatory cytokine production, promoted interleukin-10 production, reduced cellular damage in the peritoneal cavity, and, most importantly, significantly improved survival. The greatest effect on survival was obtained by the simultaneous inhibition of COX-1 activity and EP1 and EP3 receptor signaling. Importantly, early inhibition of PGE2pathways dramatically improved the survival of fluconazole-treated mice compared with that achieved with fluconazole treatment alone. These findings indicate that COX-1 and the EP1 and EP3 receptors mediate the downstream pathological effects of PGE2during polymicrobial IAI and may serve as effective therapeutic targets.