Blood-Retinal Barrier Compromise and Endogenous Staphylococcus aureus Endophthalmitis

Endogenous bacterial endophthalmitis (EBE) is a potentially devastating infection resulting from the migration of blood-borne organisms across a compromised blood–ocular barrier and into the eye. Endogenous bacterial endophthalmitis comprises approximately 2% to 8% of all endophthalmitis cases1 and is one of the most harmful ocular infections owing to uniformly poor visual outcomes and the possibility of bilateral blindness. Most EBE patients have an underlying disease and/or are immunocompromised.2 These conditions include endocarditis, urinary tract infections, diabetes mellitus, the presence of indwelling central venous catheters, immunosuppressive therapy, and illicit intravenous drug abuse.3 Currently, diabetes mellitus ranks among the leading predisposing diseases for EBE and is associated with 33% of cases.1,4–7 Staphylococcus aureus accounts for nearly 10% of EBE cases worldwide1 and is the leading cause of EBE in the Western hemisphere and Europe, comprising approximately 25% of these cases.1–3 In the United States, approximately 40% of EBE cases are associated with endocarditis, which is usually caused by S. aureus.3 Staphylococcus aureus is a gram-positive bacterium that normally colonizes the skin and mucosa but can cause mucosal and submucosal infections, and life-threatening systemic infections, including septicemia, endocarditis, and pneumonia.8,9 Staphylococcus aureus EBE is also frequently associated with infection of indwelling catheters and prosthetic devices in diabetics and the immunocompromised.1,7–12 Presently, methicillin-resistant S. aureus (MRSA) infections are a public health emergency owing to the refractory nature of these multidrug-resistant infections. It has been estimated that greater than 50% of S. aureus isolates from health care settings are methicillin-resistant.2 MRSA infections among persons with functioning immune systems are being reported with increasing frequency.13 Paralleling the rise in the frequency of MRSA infections is an increase in the number of MRSA endophthalmitis cases.10,14 Major et al.10 have reported that MRSA strains account for 41% of all types of endophthalmitis caused by S. aureus and cause a similar percentage of cases of S. aureus EBE. Moreover, this group has found that among the MRSA isolates, approximately 38% are also resistant to commonly used fourth-generation fluoroquinolones (gatifloxacin and moxifloxacin) used to treat ocular infections.10 Case studies have revealed that only 24% to 38% of MRSA EBE infections result in a final visual acuity better than 20/200.2 Visual acuity outcomes of S. aureus EBE are consistently poor. However, no difference between the final Snellen visual acuity of MRSA- and methicillin-sensitive S. aureus–infected eyes has been observed.10 Currently, a limited understanding exists regarding the interactions between the host and bacterial factors that contribute to the development of EBE. The factors contributing to the migration of S. aureus into the eye resulting in EBE have not been analyzed. It has been suggested that diabetes ranks among the leading underlying factors associated with EBE because of the immunologic and architectural changes in the eye that occur during the progression of diabetes.6,15–17 These changes include increases in vascular endothelial growth factor, IL-1β, IL-6, IL-8, and TNF-α in diabetic retinas that lead to angiogenesis and a breakdown in the blood–retinal barrier (BRB).18 Further, increases in neutrophil adhesion to the endothelial wall due to upregulation of intercellular adhesion molecule 1 (ICAM-1) and CD18 lead to endothelial cell injury and death.19–22 Architecturally, pericyte death and basement membrane thickening lead to capillary leakage and occlusion. These changes ultimately result in macular edema, angiogenesis, and neuroretinal degeneration.18–28 Collectively, these alterations in the diabetic ocular environment could compromise the eye's ability to prevent bacteria from entering during systemic infection. Until recently, the lack of an animal model of EBE has been largely responsible for the gaps in information on the role of bacterial and host factors in the development of EBE. We have developed a murine model of diabetes-associated Klebsiella pneumoniae EBE and reported a correlation between the time from diabetes induction with streptozotocin (STZ) and the incidence of EBE.17 Further, the observed increase in infection incidence also correlates with increases in BRB permeability that occur in mice with more advanced diabetes.17 In the current study, we extended the use of our mouse model to address the hypothesis that diabetic ocular changes coincided with an increase in incidence in S. aureus EBE. Here, we showed a correlation between diabetes development and the incidence of S. aureus EBE, and further demonstrated that S. aureus possesses the capacity to cause EBE in nondiabetic, normal eyes without preexisting vascular leakage. We also showed that S. aureus is capable of inducing alterations in the tight junctions between human retinal epithelial (RPE) cells in vitro and traversing an intact RPE barrier. In conjunction with our in vivo infection data, these results support the hypothesis that the BRB compromise in diabetic mice contributes to the development of EBE and that S. aureus is capable of inducing BRB permeability on its own, causing EBE in normal and diabetic animals.