SARS-COV-2 spike protein promotes RPE cell senescence via the ROS/P53/P21 pathway

Area of Science:

• Ophthalmology
• Virology
• Cell Biology

Background:

• SARS-CoV-2 infection is linked to cellular senescence.
• The role of the SARS-CoV-2 spike protein (S-protein) in retinal pigment epithelium (RPE) cell senescence is not fully understood.
• Potential implications for age-related macular degeneration (AMD) warrant investigation.

Purpose of the Study:

• To investigate the role of SARS-CoV-2 S-protein in inducing RPE cell senescence.
• To elucidate the molecular mechanisms underlying S-protein-induced senescence.
• To assess the in vivo effects of S-protein on retinal senescence.

Main Methods:

• ARPE-19 cells were treated with S-protein or S-protein overexpression.
• Cell proliferation, cell cycle, SA-β-Gal staining, and senescence markers (p53, p21, inflammatory factors, ROS) were assessed.
• ER stress markers (BIP, CHOP, ATF3, ATF6) and NF-κB pathway activation were analyzed.
• In vivo studies involved intravitreal injection of S-protein in zebrafish.

Main Results:

• S-protein administration/overexpression decreased ARPE-19 cell proliferation and induced G1 cell cycle arrest.
• S-protein increased SA-β-Gal positive cells, p53, p21, inflammatory factors (IL-1β, IL-6, IL-8, ICAM, VEGF), and ROS.
• ROS elimination (NAC) or p21 knockdown diminished S-protein-induced senescence.
• S-protein colocalized with ER, upregulated ER stress markers, and induced p65 nuclear translocation.
• NF-κB inhibition reduced S-protein-mediated senescence.
• Intravitreal S-protein injection upregulated senescence markers in zebrafish retina.

Conclusions:

• SARS-CoV-2 S-protein induces RPE cell senescence in vitro and retinal senescence-associated factors in vivo.
• Mechanisms involve activation of ER stress, ROS production, and NF-κB signaling.
• Findings suggest a potential link between SARS-CoV-2 infection and AMD development.