Bloodstream-To-Eye Infections Are Facilitated by Outer Blood-Retinal Barrier Dysfunction
Bloodstream-To-Eye Infections Are Facilitated by Outer Blood-Retinal Barrier Dysfunction
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DOI：
10.1371/journal.pone.0154560
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发表时间：
2016-05-19
期刊：
影响因子：
3.7
通讯作者：
Callegan, Michelle C.
中科院分区：
文献类型：
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作者：
Coburn, Phillip S.;Wiskur, Brandt J.;Callegan, Michelle C.
血-视网膜屏障(BRB)的功能是维持眼睛的免疫豁免权，这是正常视力所必需的。外层BRB是由紧密相关的视网膜色素上皮(RPE)细胞形成的，这些细胞限制了视网膜环境中的运输，维持了视网膜的功能和活力。糖尿病和糖尿病视网膜病变引起的视网膜微血管并发症和RPE功能障碍导致BRB的通透性改变，从而损害屏障功能。糖尿病是内源性细菌性眼内炎(EBE)的主要易感疾病，EBE是一种由细菌从血液侵入眼睛而引起的致盲性眼内感染。然而，大量的EBE病例发生在非糖尿病患者中。在这项工作中，我们假设外BRB的功能障碍可能与EBE的发展有关。为了在体内破坏外BRB的RPE成分，给C57BL/6J小鼠注射了碘酸钠(NaIO3)。给NaIO3处理和未处理的小鼠静脉注射108个金黄色葡萄球菌或肺炎克雷伯菌的集落形成单位(CFU)。感染肺炎克雷伯菌和金黄色葡萄球菌后，NaIO_3治疗组小鼠在感染后4天和6天出现EBE，但金黄色葡萄球菌感染后EBE发生率较高。在金黄色葡萄球菌感染后的对照组小鼠中观察到了眼睛的侵袭，但在肺炎克雷伯菌感染后的对照组小鼠中没有观察到。免疫组织化学和FITC-葡聚糖偶联物对感染外源蛋白缺陷的金黄色葡萄球菌agr/sar突变体后人RPE屏障的迁移分析表明，金黄色葡萄球菌外源蛋白可能是失去紧密连接蛋白ZO-1和这一体外屏障的通透性所必需的。我们的结果支持临床发现，对于这两种病原体，导致BRB通透性的并发症增加了细菌从血流进入眼睛的可能性。然而，对于金黄色葡萄球菌来说，BRB通透性不是EBE发生所必需的，但毒素的产生可能会促进EBE的发病。
The blood-retinal barrier (BRB) functions to maintain the immune privilege of the eye, which is necessary for normal vision. The outer BRB is formed by tightly-associated retinal pigment epithelial (RPE) cells which limit transport within the retinal environment, maintaining retinal function and viability. Retinal microvascular complications and RPE dysfunction resulting from diabetes and diabetic retinopathy cause permeability changes in the BRB that compromise barrier function. Diabetes is the major predisposing condition underlying endogenous bacterial endophthalmitis (EBE), a blinding intraocular infection resulting from bacterial invasion of the eye from the bloodstream. However, significant numbers of EBE cases occur in non-diabetics. In this work, we hypothesized that dysfunction of the outer BRB may be associated with EBE development. To disrupt the RPE component of the outer BRB in vivo, sodium iodate (NaIO3) was administered to C57BL/6J mice. NaIO3-treated and untreated mice were intravenously injected with 108 colony forming units (cfu) of Staphylococcus aureus or Klebsiella pneumoniae. At 4 and 6 days postinfection, EBE was observed in NaIO3-treated mice after infection with K. pneumoniae and S. aureus, although the incidence was higher following S. aureus infection. Invasion of the eye was observed in control mice following S. aureus infection, but not in control mice following K. pneumoniae infection. Immunohistochemistry and FITC-dextran conjugate transmigration assays of human RPE barriers after infection with an exoprotein-deficient agr/sar mutant of S. aureus suggested that S. aureus exoproteins may be required for the loss of the tight junction protein, ZO-1, and for permeability of this in vitro barrier. Our results support the clinical findings that for both pathogens, complications which result in BRB permeability increase the likelihood of bacterial transmigration from the bloodstream into the eye. For S. aureus, however, BRB permeability is not required for the development of EBE, but toxin production may facilitate EBE pathogenesis.