Monday , October 25 2021

A new study has found that SARS-CoV-2 causes retinal infection



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Can Corona Disease 2019 (COVID-19) Affect The Eye? New research suggests that Corona 2 virus severe respiratory syndrome (SARS-CoV-2) can enter the eye and infect photoreceptor cells and retinal ganglion cells. In addition, SARS-CoV-2 infection increases the expression of several inflammatory genes, including cytokine interleukin 33 (IL33), which is linked to COVID-19 disease and retinal degeneration.

Antibodies that block the ACE2 receptor reduce retinal cell infection, indicating that SARS-CoV-2 infection acts ACE2-dependent.

The study “SARS-CoV-2 infects and replicates photoreceptor cells and retinal ganglion cells of human retinal organoids” is published on preview bioRxiv* Server.

Study: SARS-CoV-2 infects and replicates photoreceptor cells and retinal ganglion cells of human retinal organoids.  Image credit: hispan / Shutterstock

Researchers find evidence for SARS-CoV-2 in the human retina

The researchers exposed adult retinal organoids to SARS-CoV-2 and then incubated the organoids for different periods of time to observe the infection and the rate of copying of the virus.

SARS-CoV-2 did indeed infect retinal cells, as confirmed by PCR examination. A viral plaque test detected viral plaques in the retinal cells infected with SARS-CoV-2, indicating that SARS-CoV-2 was successfully replicated in human retinal tissue.

Viral titer increased after 48 hours. However, titer levels returned after three days.

Immunofluorescent captured the presence of SARS-CoV-2 nucleocapsid-positive cells in retinal organoids.

Cells infected with SARS-CoV-2 appear to affect older retinal organoids compared to younger retinal organoids. In adult organoids, SARS-CoV-2 is more likely to affect the external retina. Younger retinal organoids were infected with SARS-CoV-2 in the inner retina.

SARS-CoV-2 infects mature retinal ganglion cells and photoreceptors

The findings suggest that various cells in the retina are susceptible to SARS-CoV-2 infection.

The cells that may be infected with SARS-CoV-2 were retinal ganglion cells.

In smaller numbers, OTX2 + photoreceptors, slightly bipolar cells, and AP2A + amacrine cells were tested positive for the SARS-CoV-2 nucleocapsid protein. There were even fewer VSX2 + progenitor cells infected with SARS-CoV-2.

Retinal organoids derived by iPSC can be infected by SARS-CoV-2 Retinal organoids on day 50 of differentiation are presented as containing VSX2 + (green) ancestors in retina and PAX6 + (white) / VSX2-Amcarine and retinal ganglion cells (RGCs) (A).  On day 143 of differentiation, the organoids are presented as layered structure organizers and contain AP2a + (white) and horizontal cells, CRALBP + (red) Muller glial cells, and OTX2 + (green) cells (B).  The drawing in (B) describes the types of cells and the structure of the vertebral retina.  ONL: Outer nuclear layer;  OPL: outer female layer;  INL: Inner nuclear layer;  IPL: inner porous layer;  GCL: Ganglion cell layer.  On day 143 of differentiation, the light receptors in the organoids are stained against the sensitive proteins L / M-OPN (white) and RHODOPSIN (RHO, red) (C).  Real-time PCR detected SARS-CoV-2 genomic RNA within retinal organoids treated with SARS-CoV-2 but not in controls on day 125 (D).  Viral plaque test was used to evaluate viral titrations in SARS-CoV-2-treated organoids on day 125 (E).  Each repetition (N = 2) in (D) and (E), is a separate group of five infected or uninfected organs in a separate well.  Immunofluorescence analysis was used to detect SARSCoV-2 nucleocapsid (N) positive cells in infected organoids at day 130 (F) or 160 (G) of differentiation.

Retinal organoids derived by iPSC can be infected by SARS-CoV-2 Retinal organoids on day 50 of differentiation are presented as containing VSX2 + (green) ancestors in retina and PAX6 + (white) / VSX2-Amcarine and retinal ganglion cells (RGCs) (A). On day 143 of differentiation, the organoids are presented as layered structure organizers and contain AP2a + (white) and horizontal cells, CRALBP + (red) Muller glial cells, and OTX2 + (green) cells (B). The drawing in (B) describes the types of cells and the structure of the vertebral retina. ONL: Outer nuclear layer; OPL: outer female layer; INL: Inner nuclear layer; IPL: inner porous layer; GCL: Ganglion cell layer. On day 143 of differentiation, the light receptors in the organoids are stained against the sensitive proteins L / M-OPN (white) and RHODOPSIN (RHO, red) (C). Real-time PCR detected SARS-CoV-2 genomic RNA within retinal organoids treated with SARS-CoV-2 but not in controls on day 125 (D). Viral plaque testing was used to evaluate viral titrations in SARS-CoV-2-treated organoids on day 125 (E). Each repetition (N = 2) in (D) and (E), is a separate group of five infected or uninfected organs in a separate well. Immunofluorescence analysis was used to detect SARSCoV-2 nucleocapsid (N) positive cells in infected organoids at day 130 (F) or 160 (G) of differentiation.

SARS-CoV-2 increases the expression of inflammatory genes

The study observed upregulation of 366 genes and downregulation of 393 genes.

“The five categories of the most enriched biological process in this analysis were ‘potassium ion transport’, ‘cellular response to cytokine stimulation’, ‘cellular response to BMP stimulation’, ‘metal ion transport’ and ‘cytokine-mediated signaling pathway’, the researchers explained.

An increase in cytokine-associated gene expression indicates an immune response in response to the SARS-CoV-2 virus.

Genes associated with the JAK-STAT signaling pathway – pathway involved in inflammation and congenital antiviral interferon response – are enriched even after SARS-CoV-2 infection.

The researchers suggest that the adaptation of genes associated with potassium ion transport may be related to the low potassium levels observed during COVID-19 disease.

In addition, SARS-CoV-2 appears to increase IL33 gene expression because it was the most ordered cytokine in all of the official infected organoids. IL33 is involved in retinal inflammation and photoreceptor deterioration.

NLRP1 is another regulated inflammatory gene observed during SARS-CoV-2 infection. In addition, the gene is associated with retinal ganglion cell death during acute glaucoma.

SARS-CoV-2, like other corona viruses, may adversely affect cell cycle and DNA damage response. Decreased regulation of genes involved in DNA metabolism, repair and re-integration was observed in retinal organoids after infection.

ACE2 receptor blockade reduces SARS-CoV-2 infection

ACE2 mRNA levels are low in the human retina. However, ACE2 protein is abundant.

SARS-CoV-2 infection did not alter ACE2 expression, indicating a lack of ACE2 regulation in retinal cells.

When researchers treated infected retinoids with an antibody to ACE2, the number of nucleocapsid SARS-CoV-2 proteins in infected cells decreased significantly.

Based on the results, the researchers conclude that SARS-CoV-2 infection and retinal cell duplication are dependent on ACE2 receptors.

Drugs designed for ACE2 receptors may help treat COVID-19 patients with retinal symptoms.

*important message

bioRxiv Publishes preliminary scientific reports that are not reviewed by colleagues and therefore should not be considered conclusive, facilitating clinical practice / behavior related to health or treating them as established information.

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