Findings from a recent study published in PLOS Pathogens demonstrated that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes coronavirus disease 2019 (COVID-19), can breach the blood-retina barrier (BRB) and potentially cause long-term ocular damage.
Give me some background.
SARS-CoV-2 is known to cause several ocular abnormalities and vision impairment in COVID-19 patients.
However, SARS-CoV-2’s ability to invade ocular tissue and its effects on ocular health remain unclear.
Talk about the BRB.
The BRB is designed to prevent microbial pathogens from reaching the retina, where they could trigger an inflammatory response that could potentially result in vision loss.
Previous studies have suggested that the eye may serve as a potential route for SARS-CoV-2 transmission.
Thus: A research team from the University of Missouri School of Medicine sought to investigate the interaction between SARS-CoV-2 and cells lining the BRB.
Now this study.
Researchers utilized humanized K18-hACE2 mouse models to evaluate the impact of SARS-CoV-2 on ocular health from ocular and intranasal exposure to the virus.
They also utilized ocular cell cultures to evaluate how SARS-CoV-2 interacts with cells lining the BRB.
Back up: What is a humanized k18-hACE2 mouse?
These are mice that express human angiotensin-converting enzyme 2 (hACE2), the receptor used by SARS-COV to gain cellular entry, and human cytokeratin 18 (K18) promoter, which directs expression to the epithelia—including the airway epithelia where infections typically begin.
Meaning: This makes the mice susceptible to SARS-CoV-2 and helpful for studying antiviral therapies for COVID-19.
Findings?
SARS-CoV-2 ocular exposure was found to not cause lung infection or lethal illness in K18-hACE2 mice—despite the long-term presence of viral remnants in ocular tissues.
Conversely, intranasal exposure resulted not only in the presence of SARS-CoV-2 spike (S) protein in different ocular tissues but also induced a hyperinflammatory immune response in the retina.
Further, in mouse eyes, long-term exposure to viral S-protein caused:
- Microaneurysm
- Retinal pigment epithelium (RPE) mottling
- Retinal atrophy
- Retinal artery and vein occlusion
- Vascular leakage
What about the BRB?
The cells lining the BRB, outer barrier, RPE, inner barrier, and the retinal vascular endothelium were highly permissive (i.e. supported the growth or genetic replication of the virus) to SARS-CoV-2 replication.
These cells showed induced expression of viral entry receptors and increased susceptibility to SARS-CoV-2-induced cell death.
However, the corneal epithelium was found to be resistant to SARS-CoV-2 infection and ocular exposure to the virus failed to cause lung pathology or life-threatening illness.
Anything else?
Hyperglycemic conditions (i.e., diabetes) increased the viral entry receptor expression, infectivity, and susceptibility of SARS-CoV-2-induced cell death in BRB cells—confirming the reported heightened pathological manifestations in comorbid patient populations.
Expert opinion?
Pawan Kumar Singh, PhD, corresponding author of the study, stated: “For those who have been diagnosed with COVID-19, we recommend you ask your ophthalmologist to check for signs of pathological changes to the retina.”
This also applies to asymptomatic patients, as they could suffer damage to the eyes over time due to COVID-19-associated complications.
Significance?
Although it is known that viruses and bacteria can breach the blood-retina barrier in immunocompromised patients, this study is the first to indicate that SARS-CoV-2 can breach the barrier in healthy patients—causing an infection that manifests inside the eye itself.
Tie it all together for me.
These findings suggest that, in humanized mouse models, SARS-CoV-2 can infect the eye following both intranasal and ocular exposure.
Intranasal exposure led to the dissemination of the virus to the eye, while ocular exposure did not transmit to distal organs or cause lethal infections.
Additionally, intranasal exposure resulted in hyperinflammatory retinal responses and increased permissivity of the cells lining the BRB—indicating a systemic spread of the virus through the BRB.
Finally, ocular manifestations of SARS-CoV-2 infections were exacerbated in hyperglycemic patients.
Next steps?
The next step is to elucidate the cellular and molecular mechanisms of how SARS-CoV-2 breaches the BRB and associated pathological consequences, with the aim of developing therapies to prevent and treat COVID-19-induced ocular complications prior to vision loss.