Abstract
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.
Highlights
The blood-retinal barrier (BRB) is a component of ocular immune privilege and serves to protect the delicate, nonregenerative neural retina from the immune system and bloodborne pathogens
After 6 days postinfection, the mean cfu per eye for the K. pneumoniae-infected mice was 1.16 x 102, and for S. aureus-infected mice was 2.58×102. These results indicated that intraocular infection with either K. pneumoniae or S. aureus can occur after specific disruption of the retinal pigment epithelium (RPE) component of the outer BRB in nondiabetic mice at incidences similar to that reported in diabetic mice [28,29]
The frequency of S. aureus endogenous bacterial endophthalmitis (EBE) in 5-month diabetic mice was comparable to previous observations for K. pneumoniae EBE, the incidence of S. aureus EBE in 3-month diabetic mice was 2.5-fold greater
Summary
The blood-retinal barrier (BRB) is a component of ocular immune privilege and serves to protect the delicate, nonregenerative neural retina from the immune system and bloodborne pathogens. The BRB consists of inner (endothelial cells, pericytes, and astrocytes) and outer (retinal pigment epithelial cells) components. The retinal pigment epithelium (RPE) consists of a single layer of cuboidal pigmented cells whose specific functions are critical for neural retina homeostasis. The RPE maintains the retinal environment by limiting transport across the retina, maintaining a tight barrier to choroidal bloodborne substances [1,2]. The endothelial cells lining the capillaries supplying the retina with oxygen and nutrients form the inner BRB, which exhibits selective permeability to small molecules, and is virtually impermeable to large macromolecules [3]. During the development of diabetes and its ocular complication diabetic retinopathy, changes occur in the BRB which result in greater vascular permeability and loss of RPE function [4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20]
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