The SARS-CoV-2 virus, which infects the upper respiratory tract and multiple organs, can cause a reaction within the body in which immune-cell networks are derailed and the cell-signaling proteins known as cytokines are churned up into a perfect storm that leads to many of the problems that arise in the COVID-19 disease. Knowing about this cytokine storm offers us some hope by presenting researchers with a potential target for pharmaceutical interventions that might control the symptoms of the disease and lead to better outcomes for patients.

Clemens A. Schmitt, Charité – Universitätsmedizin, Berlin Institute of Health (BIH), Molekulares Krebsforschungszentrum (MKFZ), and Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association, all Berlin, Germany, Johannes Kepler University, Linz, Austria, and colleagues have found evidence of how the virus triggers cellular senescence in infected cells. In cellular senescence, cells stop dividing as a response to damage or stress.

The researchers found that virus-induced senescence (VIS) is indistinguishable from senescence triggered in other ways and is accompanied by a stress response involving cytokine release and the release of extracellular matrix-active factors and pro-coagulatory mediators. COVID-19 patients show markers of this process both in the mucous membranes of their airways and through elevated serum levels of the relevant factors.

Possible Therapeutic Target

The team mirrored several of the hallmark features of COVID-19 infection in vitro, such as macrophage and neutrophil infiltration, damage to endothelial layers, and thrombosis within affected lung tissue. They were able to carry out in vitro assays that showed the kind of macrophage activation expected in the disease and the senescence of infected cells. They showed that the use of so-called senolytic drugs, such as Navitoclax and Dasatinib/Quercetin, could then eliminate infected cells that had gone into a senescent state.

This finding suggests that these and related drugs may have the capacity to target VIS cells, and thus, halt the escalation of the cytokine response and consequent organ damage. Tests of those drugs in hamster and mouse models of SARS-CoV-2 infection showed that they can mitigate the kind of lung disease seen in COVID-19 as well as reduce the inflammation that occurs.

Both Vaccines and Treatment Options are Needed

Vaccination programs have reached high levels of COVID-19 vaccinations in many countries. However, not everyone has access to vaccination, and many millions of people remain unprotected. Moreover, there are concerns that even those people who have been fully vaccinated against SARS-CoV-2 can remain susceptible to infection. While there are discussions concerning administering a booster dose of a vaccine to those in the older age brackets or with other risk factors, there remains a fundamental need for pharmaceutical interventions that can be used to treat the disease if it occurs.

“Senolytic targeting of virus-infected cells [offers] a novel treatment option against SARS-CoV-2 and perhaps other viral infections,” the team suggests. They also point out that the strategy might be useful should a similar virus emerge in the future and threaten another global pandemic.

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• Virus-induced senescence is driver and therapeutic target in COVID-19,
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