BREAKING! German Study Shows SARS-CoV-2 Can Infect And Replicate In Retinal Cells With Implications Of Eye Issues For Long COVID!

A new study by researchers from Max Planck Institute for Molecular Biomedicine has discovered that the SARS-CoV-2 coronavirus is able to infect and replicate in the photoreceptor and also retinal ganglion cells of human retinal organoids.

Alarmingly the study findings not only suggest a retinal involvement in COVID 19 but also emphasize the need to monitor retinal pathologies as potential sequelae of long COVID.
 
Past research has pointed to retinal involvement in COVID 19 disease, yet many questions remain regarding the ability of SARS-CoV-2 to infect and replicate in retinal cells and its effects on the retina. https://www.thailandmedical.news/news/covid-19-news-italian-researchers-find-that-sars-cov-2-can-affect-the-retina-in-the-eyes
 
https://www.thailandmedical.news/news/covid-19-and-eyes-doctors-report-case-of-retinal-vein-occlusion-due-to-covid-19-in-patient-more-cases-of-eyes-being-attacked-by-sars-cov-2-emerging
 
https://www.thailandmedical.news/news/covid-19-clinical-care-brazilian-study-finds-retinal-lesions-in-patients-with-severe-covid-19
 
The study team used human stem cell derived retinal organoids to study retinal infection by the SARS-CoV-2 virus.
 
The SARS-CoV-2-Retina study findings confirmed that Indeed SARS-CoV-2 can infect and replicate in retinal organoids, as it is shown to infect different retinal lineages, such as retinal ganglion cells and photoreceptors.
 
The study also alarmingly showed that SARS-CoV-2 infection of retinal organoids also induced the expression of several inflammatory genes, such as interleukin 33, a gene associated with acute COVID 19 disease and retinal degeneration.
 
The study findings also demonstrated that the use of antibodies to block the ACE2 receptor significantly reduces SARS-CoV-2 infection of retinal organoids, indicating that SARS-CoV-2 infects retinal cells in an ACE2 dependent manner.
 
The study findings were published on a preprint server and are currently being peer reviewed. https://www.biorxiv.org/content/10.1101/2021.10.09.463766v1
 
Typically, retinal organoids show high similarity to the developing human retina in both morphology and transcriptome, rendering them a potent model for studying the retinal involvement in COVID-19.
 
The study findings show that SARS-CoV-2 itself infects retinal organoids, and more importantly the first evidence that SARS-CoV-2 can actively replicate in retinal tissue.
 
Interestingly, younger retinal organoids appeared to be more permissive to infection than older ones.
 
Past studies showed t hat TMPRSS2 expression, which is known to be important in SARS-CoV-2 infection, appears to be decreased in retinal organoids over time. This might suggest that more mature retinal cells are less likely to be infected by SARS-CoV-2 because of changes in TMPRSS2 expression.
However, the mRNA expression of TMPRSS2 in the retinal organoids used in the study was extremely low on day 80, suggesting that there is minimal involvement of TMPRSS2 in retinal SARS-CoV-2 infection.
 
In older retinal organoids, mature retinal cells were also infected, albeit at a lower number, indicating that mature retinal cells are still susceptible to SARS-CoV-2 infection.
 
In fact, in the organoids, progenitor cells were less likely to be infected than differentiated neurons, emphasizing the susceptibility of retinal neurons to infection. As retinal organoids differentiate, the number of cells contained therein increases, potentially increasing the organoid density. As organoids lack vascularization, an increase in their density and size might decrease the permeability of the inner layers to SARS-CoV-2 and decrease the likelihood of viral infection of inner retinal cells. Moreover, changes in the cell type composition might affect the infectability of the organoids. Loss of RGCs is known to occur during maturation of human retinal organoids, with nearly complete depletion of RGCs at the late stages.
 
The observed decrease in SARS-CoV-2–infected cells during retinal organoid maturation might be related to changes in the number of RGCs over time.
 
Although the study identified SARS-CoV-2–infected cells from different retinal lineages, RGCs were significantly more likely to be infected.
 
Interestingly, many of the retinal symptoms associated with COVID-19, such as lesions in the GCL and swelling of the optic nerve, are related to RGCs. https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)31014-X/fulltext
 
https://pubmed.ncbi.nlm.nih.gov/32648939/
Pathology of the GCL could be the result of several issues, such as vascular dysfunction or increase in ocular pressure, and thus might be a secondary effect to other symptoms of the disease.
 
However, as SARS-CoV-2 targets organoids RGCs, infection of RGCs may have such direct pathological consequences. RGCs are the cells that generate the optic nerve and connect the retina to the rest of the CNS. Past studies have shown that viruses, such as the herpes simplex virus type 1, can be anterogradely transferred from the retina through the optic nerve into its targets in the brain.
 
Hence considering this, the possibility that the retina represents a potential entry route for SARS-CoV-2 into the rest of the CNS should be considered.
 
Another study had also suggested that SARS-CoV-2 can infect many non-retinal ocular cell tissues such as the cornea, the sclera, the choroid, the limbus and the RPE, indicating the possibility of SARS-CoV-2 infection through the eye. https://pesquisa.bvsalud.org/global-literature-on-novel-coronavirus-2019-ncov/resource/pt/covidwho-1230788
 
All these suggest a direct route for SARS-CoV-2 infection from exposed ocular surface tissues like the cornea to the CNS through the retina.
 
The study findings also suggest that the infection of retinal organoids results in the upregulation of several inflammatory genes. The most significantly upregulated cytokine in infected retinal organoids was IL33.
 
The study findings also suggest that SARS-CoV-2 infection of retinal cells results in an inflammatory response of immune system factors such as IL33 and NLRP1 which are involved in retinal degenerative diseases causing irreversible blindness. Cytokines that were up-regulated in the infected organoids, may prove to be worthy candidates for further studies regarding COVID19 retinal pathology.
 
Detailed comparison of the DE genes in retinal organoids and choroid plexus organoids identified enrichment of TGFb response genes among genes which were induced in the retinal but not in the choroid plexus organoids, suggesting that SARS-CoV-2 infection may induce differential TGFb response in different systems.
 
Also the differences in TGFb response of retinal and choroid plexus organoids to SARS-CoV-2 infection may be related to the immunosuppressive role of TGFb.
 
SARS-CoV-2 retinal infection is dependent on ACE2. ACE2 protein has been identified in human retinas and retinal organoids. https://www.mdpi.com/1422-0067/22/3/1320
 
https://pubmed.ncbi.nlm.nih.gov/17591902/
 
The study findings indicate that the infection of retinal cells can be blocked by using anti-ACE2 antibodies. Thus, the infection of retinal cells most likely is primarily dependent upon functional ACE2 receptors.
 
The possibility of blocking retinal infection by using ACE2 antibodies may also be helpful for the development of drugs in the treatment of SARS-CoV-2 retinal infection.
 
In conclusion, the study data indicates that SARS-CoV-2 can actively infect retinal cells in an ACE2- dependent manner. Further studies should consider the possibility that neuro-retinal infection leads to retinal symptoms in patients with COVID-19 and perhaps examine potential treatment options. SARS-CoV-2–dependent photoreceptor and/or RGC degeneration can cause permanent visual impairment or even blindness.

Although data suggesting vision impairment in patients with COVID-19 is scarce, it should be noted that visual impairment and subsequent blindness from retinal degenerative diseases may become evident only after a long course of progression. Long-COVID or Post-Covid-Syndrome–related vision impairment or even blindness may occur at a much later time point after an acute SARS-CoV-2 infection.
 
Importantly the induction of inflammatory genes that are related to retinal degeneration in the organoids should prompt further investigation of the association between SARS-CoV-2 infection and retinal degenerative diseases.
 
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