Virus-induced senescence is correlated with DNA damage and loss of neuronal networks mediated by the pro-inflammatory activation of the cGAS-STING pathway

Viral infections can trigger the activation of several cellular pathways, which can contribute to the restriction of virus replication but also induce stress-responses such as virus-induced senescence (VIS). Yet, the direct relationship between virus infection and senescence induction is far from being understood. Cellular senescence is a direct consequence of DNA damage response (DDR). While the interplay between DNA viruses and DDR has been studied, the impact of RNA viruses is less known.

Here, we show that Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) infection causes DNA damage and elicits an altered DDR in vitro, in vivo and in COVID-19 patients. SARS-CoV-2 causes a reduction in CHK1 and a consequent decrease in RRM2, causing dNTP shortage and impairment of the S-phase progression associated with DNA damage accumulation, cGAS activation and senescence. SARS-CoV-2 infection has been associated with neurological symptoms characteristic of long-lasting coronavirus disease (COVID). Activated glial cells are key players in response to central nervous system infection, yet are implicated in inflammation and neurodegeneration. Interestingly, glial cells showed signs of senescence and activation of the cGAS-STING pathway. Then, we investigated if glial cell activation could affect the function of neuronal networks. Primary rat cortical cultures seeded on multielectrode arrays (MEAs) were used to monitor electrical activity. Effective SARS-CoV-2 infection of the glia led to a major loss of synaptic connections, an increase in cGAS-associated pro-inflammatory response and an increment of DNA damage foci. Finally, we demonstrated that an antagonist of the cGAS-STING pathway was able to rescue the decrease in electrical activity post-infection.

Tick-borne encephalitis virus (TBEV) is a growing health concern and causes severe and long-lasting sequelae, including permanent neurological complications. Therefore, we studied neurons and glial cells during infection. Similar to COVID-19, TBEV induced senescence, activation of the pro-inflammatory cGAS-STING pathway, an increase in DNA damage foci and cellular senescence.