Retinal and Choroidal Pathologies in Aged BALB/c Mice Following Systemic Neonatal Murine Cytomegalovirus Infection.

Although pathologies associated with acute virus infections have been extensively studied, the effects of long-term latent virus infections are less well understood. Human cytomegalovirus, which infects 50% to 80% of humans, is usually acquired during early life and persists in a latent state for the lifetime. The purpose of this study was to determine whether systemic murine cytomegalovirus (MCMV) infection acquired early in life disseminates to and becomes latent in the eye and if ocular MCMV can trigger in situ inflammation and occurrence of ocular pathology. This study found that neonatal infection of BALB/c mice with MCMV resulted in dissemination of virus to the eye, where it localized principally to choroidal endothelia and pericytes and less frequently to the retinal pigment epithelium (RPE) cells. MCMV underwent ocular latency, which was associated with expression of multiple virus genes and from which MCMV could be reactivated by immunosuppression. Latent ocular infection was associated with significant up-regulation of several inflammatory/angiogenic factors. Retinal and choroidal pathologies developed in a progressive manner, with deposits appearing at both basal and apical aspects of the RPE, RPE/choroidal atrophy, photoreceptor degeneration, and neovascularization. The pathologies induced by long-term ocular MCMV latency share features of previously described human ocular diseases, such as age-related macular degeneration.

Inflammation and outer blood-retina barrier (BRB) compromise following choroidal murine cytomegalovirus (MCMV) infections.

Purpose: The purpose of this study was to determine whether the blood-retina barrier is compromised by choroidal murine cytomegalovirus (MCMV) infection, using electron microscopy. Methods: BALB/c mice were immunosuppressed with methylprednisolone and monoclonal antibodies to CD4 and CD8. At several time points post-MCMV intraperitoneal inoculation, the eyes were removed and analyzed with western blotting and immunoelectron microscopy for the presence of MCMV early antigen (EA) and the host protein RIP3. Posterior eyecups from RIP3-/- and RIP3+/+ mice were cultured and inoculated with MCMV. At days 4, 7, and 11 post-infection, cultures were collected and analyzed with plaque assay, immunohistochemical staining, and real-time PCR (RT-PCR). Results: MCMV EA was observed in the nuclei of vascular endothelial cells and pericytes in the choriocapillaris. Disruption of Bruch's membrane was observed, especially at sites adjacent to activated platelets, and a few RPE cells containing some enlarged vesicles were found directly beneath disrupted Bruch's membrane. Some virus particles were also observed in the enlarged vesicles of RPE cells. Levels of the RIP3 protein, which was observed mainly in the RPE cells and the basement membrane of the choriocapillaris, were greatly increased following MCMV infection, while depletion of RIP3 resulted in greatly decreased inflammasome formation, as well as expression of downstream inflammation factors. Conclusions: The results suggest that systemic MCMV spreads to the choroid and replicates in vascular endothelia and pericytes of the choriocapillaris during immunosuppression. Choroidal MCMV infection is associated with in situ inflammation and subsequent disruption of Bruch's membrane and the outer blood-retina barrier.

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

Zika virus (ZIKV) is an important pathogen that causes not only neurologic, but also ocular, abnormalities. Thus, it is imperative that models to study ZIKV pathogenesis in the eye are developed to identify potential targets for interventions. Here, we studied ZIKV interactions with human retinal cells and evaluated ZIKV's pathobiology in mouse eyes. We showed that cells lining the blood-retinal barrier (BRB), the retinal endothelium, and retinal pigment epithelium (RPE) were highly permissive and susceptible to ZIKV-induced cell death. Direct inoculation of ZIKV in eyes of adult C57BL/6 and IFN-stimulated gene 15 (ISG15) KO mice caused chorioretinal atrophy with RPE mottling, a common ocular manifestation of congenital ZIKV infection in humans. This response was associated with induced expression of multiple inflammatory and antiviral (IFNs) response genes in the infected mouse retina. Interestingly, ISG15 KO eyes exhibited severe chorioretinitis, which coincided with increased retinal cell death and higher ZIKV replication. Collectively, our study provides the first evidence to our knowledge that ZIKV causes retinal lesions and infects the cells lining the BRB and that ISG15 plays a role in retinal innate defense against ZIKV infection. Our mouse model can be used to study mechanisms underlying ZIKV-induced chorioretinitis and to gauge ocular antiviral therapies.

Lack of herpes virus DNA in choroidal tissues of a patient with serpiginous choroiditis.

OBJECTIVE: To investigate the role of herpes viruses in the etiology of serpiginous choroiditis. DESIGN: Interventional case report. PARTICIPANT: A 59-year-old male patient with long-term history of serpiginous choroiditis. INTERVENTION: The patient's affected eye was obtained during autopsy. Polymerase chain reaction was performed in the microdissected choroidal tissues. RESULTS: Histopathologic examination demonstrated active inflammation with lymphocytic infiltration of the choroid. No viral DNA was amplified using pairs of herpes simplex virus (HSV) P1/P2 (for HSV-1, HSV-2, Epstein-Barr virus [EBV], cytomegalovirus [CMV] and human herpes virus [HHV]-8), and varicella-zoster virus [VZV] P1/P2 (for VZV, HHV-6, HHV-7) in the infiltrating lymphocytes or choroidal tissues. CONCLUSIONS: The current observation suggests a lack of a role for herpetic viral etiology in the etiopathogenesis of serpiginous choroiditis.

Reducing chorioretinal viral counts with intravitreal foscarnet injections in a rabbit model of Herpes simplex virus type-1 retinitis.

The efficacy of intravitreal foscarnet injections was evaluated in a rabbit model of Herpes simplex virus type-1 (HSV-1) retinitis. In untreated infected animals, viral titration revealed that the optic chiasm, vitreous and chorioretina were positive for HSV-1. On the other hand, foscarnet treatment significantly decreased the viral count in the chorioretina when compared to the untreated group. Immunolocalization of HSV in untreated infected animals clearly showed infected cells in the outer and inner layers of the retina and also in the ciliary body of the eye. Clinical examination by indirect ophthalmoscopy indicated an absence of optic nerve congestion and a lower level of vitritis in foscarnet treated animals compared to the untreated group. It is concluded that intravitreal injections of foscarnet reduced the viral titer in the chorioretina in a rabbit model of HSV-1 retinitis. This route of administration might be valuable for the treatment of CMV retinitis in AIDS patients with sight threatening lesions or intolerance to intravenous anti-CMV drugs.

Progressive outer retinal necrosis secondary to varicella zoster virus in acquired immune deficiency syndrome.

BACKGROUND: A syndrome consisting of rapidly progressive outer retinitis in patients with suppressed immune systems has been described. The etiologic agent appears to be a member of the herpes virus family. METHODS: A 41-year-old man with acquired immune deficiency syndrome (AIDS) developed bilateral outer retinitis and choroiditis, which progressed despite antiviral treatment. A transscleral eye wall biopsy specimen and whole globe were submitted for microbiologic and histologic study. RESULTS: Polymerase chain reaction of a transscleral eye wall biopsy specimen and of the enucleated specimen determined the etiologic agent to be varicella zoster virus (VZV). Histologic studies demonstrated intranuclear inclusions consistent with viral particles in choroidal cells. CONCLUSION: Our study revealed intranuclear inclusions in choroidal cells, a previously undocumented finding in progressive outer retinal necrosis. Polymerase chain reaction was very useful in identifying the causative agent.