Bloodstream-To-Eye Infections Are Facilitated by Outer Blood-Retinal Barrier Dysfunction

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.

Classical and alternative complement activation on photoreceptor outer segments drives monocyte-dependent retinal atrophy

“…Choroidal neovascularization has been observed in a sub-population of patients diagnosed with GA and points to disruption of the outer blood-retinal barrier 6 , 7 . To address the in vivo consequences of complement activation on POS, we recapitulated RPE cell death and loss of outer blood-retina barrier (BRB) function by treating mice with NaIO 3 39 that induces death of RPE within hours 40 , 41 . This is accompanied by transient edema as measured by spectral domain-optical coherence imaging (SD-OCT) 42 and fluorescein dye and albumin leakage 39 .…”

Zika virus infects cells lining the blood-retinal barrier and causes chorioretinal atrophy in mouse eyes

“…Previous studies from our laboratory and others have shown that BRB dysfunction allows the entry of infectious agents into the retina/vitreous cavity and causes inflammation and tissue damage (48,49). A recent study by Miner, Apte, and colleagues provided the first evidence of ZIKV RNA in the eyes of subcutaneously challenged IFNRA1 -/-mice (27), but the cellular mechanisms by which ZIKV invaded the eye were not elucidated.…”

The Pathogenesis of Staphylococcus aureus Eye Infections

“…Diabetic mice are prone to developing endogenous endophthalmitis; that is, bacteria injected intravenously can penetrate the barrier between the blood vessels and the vitreous humor. Mice not rendered diabetic demonstrated the movement of bacteria from the blood to vitreous in only 7% of the cases whereas mice rendered diabetic for 3 months experienced bacterial movement from the blood to the vitreous in 58% of the animals [ 179 , 180 ].…”