Association between SARS-cov-2 infection and development of Age-related macular degeneration (AMD)

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Unknown author - National Eye Institute of the NIH, http://www.nei.nih.gov/photo/eyedis/images/EDA22_72.jpg

A new study conducted by Chinese researchers have found the spike protein of the SARS-CoV-2 virus promotes retinal pigment epithelium (RPE) cell senescence via the ROS/P53/P21 pathway which can lead to eye macular degeneration.

The study findings were published in the peer reviewed journal: Biogerontology (Springer)
https://link.springer.com/article/10.1007/s10522-023-10019-0

SARS-CoV-2 infection attacks multiple organs, leading to acute inflammation(Guan et al. 2020) as well as the chronic complications such as chronic fibrosis in kidney and lung(Bui et al. 2021; Jansen et al. 2022). Aging increases SARS-CoV-2 infection incidence and inflammatory symptoms.

On the other hand, infection of SARS-CoV-2 and its spike protein can trigger cellular senescence, a cellular process associated with ageing and age-associated diseases such as tumor, neurodegenerative diseases, diabetics and AMD (Collado et al. 2007; Meyer et al. 2021; Tripathi et al. 2021).

Here we show that the S-protein of SARS-CoV-2 can induce ARPE-19 cell senescence in vitro by upregulating cellular ROS, ER stress, and NF-κB pathways (Figs. 3, 4, 5 and 6). Intravitreal administration of S-protein upregulates the expression of senescence-associated inflammatory factors in the zebrafish retina (Fig. 7).

These results reveal a potential association of SARS-CoV-2 infection and retinopathy.

Accumulating evidence demonstrate that increased number of senescent RPE cells are associated with AMD by producing senescence-associated cytokines, injuring the retinal barrier, and losing its endocytosis ability or vision cycle (Hjelmeland et al. 1999; Ambati et al. 2003).

The virus infection is coorelated with retinopathy, including development of AMD. For example, infection by latent CMV has been shown to promote neovascularization in VEGFA-overexpressed mice (Xu et al. 2020). Infection of HerPs/-virus -6A may be another virulent contributor to the development of AMD by downregulating complement receptor CD46 in RPE and choroid endothelial cells (Fierz 2017).

Our data suggest that the S-protein of SARS-CoV-2 may be a virulent factor in triggering retinopathy. We find that both administration of purified S-protein and ectopic expression of Flag-S-protein induce ARPE-19 cell senescence (Figs. 1 and 2). This is consistent with previous report demonstrating that the Spike protein can cause senescence in lung tumor cells in vitro (Tripathi et al. 2021).

The senescence induction by S-protein is associated with upregulation of ROS production (Fig. 3). Removing ROS by NAC reduces S-protein-induced cellular senescence and secretion of cytokines IL-1 and IL-6 (Fig. 3). SARS-Cov-2 has been shown to increase ROS by decreasing the glutathione (GSH) and increasing GSSG in infected cells.

It accomplishes this by increasing GSH efflux and/or decreasing Cysteine uptake (Bartolini et al. 2021). Our data suggest that the spike protein is one of the pathogenic factors of SARS-CoV that increases ROS.

Activation ER stress is also involved in SARS-Cov-2-induced pathological change (Bartolini et al. 2022). SARS-Cov-2 virus activates the PERK/IRE pathway via S-protein interacting with ER (Versteeg et al. 2007). We find both ectopic expression and administration of S-protein colocalized with the ER and activated ER stress by possibly activating ATF6 (Fig. 5).

S protein contains ER retention peptide, and its ER localization is regulated by viral membrane proteins E and M (Boson et al. 2021). However, the molecular mechanism underlying the traffic of administrated S-protein to ER remain unclear. Whether its receptor proteins such as laminin(Bamberger et al. 2021), ACE2, BIP are involved in the traffic of extracellular S-protein to ER remain unclear.

In addition, we studied the role of S-protein in retina by artificially administering S-protein into zebrafish vitreous humor, and found that S-protein can induce the mRNA expression of senescence-associated genes without impairing retina structure (Fig. 7). We did not observed DNA damage in S-protein treated zebrafish retina (data not shown).

This suggest the administrated S-protein can trigger the senescent phenotype, but which cell type in retina undergo senescence still remain unclear. In this zebrafish model, we only administrated S-protein once, and observation time is short. Prolonged observation of the regulatory effects of S-protein on retinopathy is necessary, which is still under investigation.


Age-related macular degeneration (ARMD) is the most common cause of blindness prevalent in developed countries, particularly in people older than 60 years. Macular degenerative changes involve the central part of the retina that is the fovea. The central vision is affected, resulting in difficulty in reading, driving, etc. It accounts for 8.7% of all types of blindness worldwide.[1]

Etiology
Several risk factors have been identified and associated with this disease.[2] Risk factors can be classified into a sociodemographic, lifestyle, cardiovascular, hormonal and reproductive, inflammatory, genetic, and ocular. Sociodemographic factors include age, gender, race, socioeconomic status.

Various studies have demonstrated an increase in prevalence as well as the progression of ARMD with age.[3] Studies have found women to be at greater risk of ARMD. However, the association is not very consistent. Both early and late ARMD are known to be common among non-Hispanic whites when compared to blacks and Hispanics.[4] Socioeconomic factors like education, income, employment status, or marital status have no association with prevalence or stage of maculopathy.[5]

Smoking is an independent risk factor for ARMD.[6] Alcohol intake is not associated with the development of ARMD.[7] The role of other lifestyle factors like obesity and physical activity in the progression of ARMD is uncertain. The Age-Related Eye Disease Study (AREDS) documented that antioxidant and zinc supplementation decreases the risk of ARMD progression and vision loss.[8] A mild to moderate association between elevated blood pressure and ARMD has been described.

Atherosclerotic lesions increase the risk of late ARMD.[9] No consistent relationship between cholesterol level and ARMD has been documented. Further studies are required to better define the mechanisms through which HDL mediates ARMD.[10] No significant relationship has been found between diabetes and ARMD.

Hormone replacement therapy or estrogen therapy in women after menopause has been found to have a potential protective effect.[11] Studies have suggested that inflammation plays a role in the pathogenesis of drusen and ARMD. Various complement-related genetic variants are associated with ARMD. These include Y402H in the CFH gene and other variants in factor B /complement component 2, complement component 3, and complement Factor I.[12]

Treatment / Management
Treatment for Dry ARMD

Dry ARMD cases require regular follow up to identify early signs of progression to an advanced stage or neovascular ARMD. Early ARMD in both eyes requires no intervention. There is no evidence to suggest that using a dietary supplement of antioxidants and minerals, reduces the risk of progression to advanced ARMD or even to intermediate ARMD among individuals with early ARMD.

However, they should be educated to undergo annual reassessments to check for progression to intermediate ARMD. Individuals with intermediate ARMD or advanced ARMD in at least one eye should be started on the dietary supplement, as suggested by AREDS.[20][21] Individuals with advanced ARMD in both eyes may consider this supplement if the individual has a visual acuity of 20/100 in at least one eye.

The formulation suggested by AREDS 1 is a daily dose of 500 mg vitamin C, 400 international units of vitamin E, 15 mg beta carotene, and a daily dose of 80 mg zinc oxide with 2 mg cupric oxide added to reduce the risk of copper-deficiency anemia. This formulation was modified by AREDS 2 to a daily dose of 500 mg vitamin C, 400 international units of vitamin E, 80 mg zinc oxide, 2 mg of cupric oxide, 10 mg of lutein, 2 mg of zeaxanthin and 1 g of omega -3 fatty acids. Beta carotene was removed as it increased the risk of lung cancer, especially in smokers. Macular pigments lutein and zeaxanthin provided an additional reduction of risk of progression of the disease.

Treatment for Neovascular ARMD

Laser Photocoagulation

Lesion sufficiently peripheral to the fovea that presents minimal risk of iatrogenic damage is the one that can undergo laser treatment. Macular photocoagulation studies revealed poor outcomes and high recurrence rates after thermal laser treatment, hence used rarely nowadays.[22]

Photodynamic Therapy

PDT was introduced in 2000 as less destructive phototherapy for treating CNV. It involves the application of light of a specific wavelength to the CNVM after administering drug verteporfin intravenously. The light incites a localized photochemical reaction in the targeted area, resulting in CNV thrombosis. The progression of CNVM is slowed, but the visual prognosis is poor. Also, PDT is known to upregulate VEGF. PDT is sparingly used nowadays except for cases of polypoidal choroidal vasculopathy.[23][24]

Antiangiogenic Therapy

Both growth-promoting, as well as growth-inhibiting factors, contribute to angiogenesis. Activators of angiogenesis include vascular endothelial growth factor (VEGF), fibroblast growth factor, transforming growth factor α and β, and angiopoietin 1 and 2. Inhibitors include thrombospondin, angiostatin, endostatin, and pigment epithelium-derived factor.

VEGF has been found to play a causal role in CNVM in ARMD. It induces vascular permeability, angiogenesis, and lymphangiogenesis and inhibits apoptosis of endothelial cells. VEGF 165 isoform is the most dominant form in ARMD. Many intravitreal anti-VEGF therapies have been approved as agents who reduce the growth of CNVM as well as help in the resolution of edema.

The first one to be approved by the Food and Drug Administration (FDA) was pegaptanib in 2004. It is an RNA oligonucleotide ligand, also known as an aptamer that binds VEGF 165.[25] Ranibizumab, Bevacizumab, and Aflibercept have supplanted pegaptanib since then.

Ranibizumab is a recombinant humanized antibody fragment (Fab) that binds VEGF. It binds to all isoforms of VEGF. Studies like MARINA, ANCHOR, PIER, and EXCITE have proved that ranibizumab administered in monthly doses causes not only reduced loss of ETDRS letters in treated eyes but also improves visual acuity in treated eyes compared to control eyes.[26][27]

Other than monthly treatment regimens, patients can opt for treatment ‘as per need’ or ‘treat and extend’ regimens. In the former regimen, after monthly injections that achieve a dry macula, treatment is reinitiated based on the recurrence of fluid. This reduces the number of injections for the patients. Treat and Extend regimen involves monthly injection till the macula is dry, then after that, the treatment interval is prolonged by two weeks till the macula remains dry. Similarly, the interval is reduced by two weeks when recurrence is noted. This, in turn, reduces the number of visits to the hospital.[28]

Aflibercept, also known as the VEGF trap, is a protein that acts as a VEGF receptor decoy. It has a combination of ligand binding elements of VEGFR1 and VEGFR2, which is fused to the constant region (Fc) of immunoglobulin IgG.

It binds both VEGF and placental growth factor and has good retinal penetration. VIEW 1 and 2 studies have documented that aflibercept is non-inferior to ranibizumab in terms of gain in the number of ETDRS letters while measuring visual acuity at the end of the treatment period. A higher dose of aflibercept administered every two months instead of monthly was also seen to be as effective as a monthly dose of ranibizumab.[29]

Bevacizumab is a full-length monoclonal antibody against VEGF, which was approved by FDA for metastatic colorectal carcinoma. It is being used as an ‘off label’ treatment for ARMD. The major advantage provided is the burden of cost per injection for the patient compared to ranibizumab and aflibercept. CATT trial compared the efficacy of bevacizumab to ranibizumab and documented that bevacizumab was found to be non-inferior to ranibizumab.[30][31][30]

The advent of intravitreal injections has reduced the need for other treatments like laser or surgery in patients with ARMD. However, Intravitreal injections do have side effects of their own. Minor complication like subconjunctival hemorrhage is common. In rare cases, major events like vitreous hemorrhage, endophthalmitis, and retinal detachment may occur. There is conflicting evidence regarding systemic adverse events like myocardial infarction and cerebrovascular accidents due to these agents. The penetration of these drugs into the retina is known to be hampered by the presence of an epiretinal membrane. Separation of the posterior hyaloid by surgery helps increase the permeability of these drugs in such cases.

Surgery is required in a few cases of ARMD, where patients present with submacular hemorrhage. Intravitreal tissue plasminogen activator with pneumatic displacement is helpful in such cases.[32] Submacular surgery involving the removal of CNVM and macular translocation surgeries have been abandoned nowadays.[33][34] A significant proportion of patients improve with the use of intravitreal agents. However, a noteworthy number of patients do progress to blindness as well. In these cases, rehabilitation with low vision aids should be considered and is found to be very effective.

reference link : https://www.ncbi.nlm.nih.gov/books/NBK560778/#:~:text=Age%2Drelated%20macular%20degeneration%20(ARMD,all%20types%20of%20blindness%20worldwide.

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