During severe COVID-19, the immune system can become overactive. This condition is accompanied by a massive release of cytokines and can lead to multiple organ failure and death.
When penetrating the cell, the virus starts the cellular senescence program. Cellular senescence is part of the natural antiviral defense mechanism. The cell cycle stops, cells secrete high levels of pro-inflammatory cytokines, acquiring a senescence-associated secretory phenotype (SASP). In response, the immune system is activated and, in order to eliminate the infection, directs immune cells to the site of inflammation. However, senescent cells are more susceptible to viruses.
SASP comprises pro-inflammatory cytokines, enzymes that destroy the cell membrane, and proteins that increase blood clotting. German scientists have suggested that cellular senescence is at the heart of the cytokine storm in COVID-19.
SARS-CoV-2 Causes Cellular Senescence
Laboratory studies on cells have confirmed that viral infection elicits a cellular response that resembles cellular senescence and is genetically dependent on SASP. Various viruses cause cellular senescence, for example, lentivirus, adeno-associated virus, vesicular stomatitis virus, and low pathogenic alpha-human coronavirus NL63.
Cellular senescence has also been observed with SARS-CoV-2. In this case, only cells expressing ACE2 aged. However, the anti-oncogenic protein p53 and the antiviral drug GS-441524 prevented senescence.
Cellular Senescence in COVID-19 Patients
Scientists analyzed tissue samples from the nasopharynx and lungs of patients who died from COVID-19. Multiple SASP factors were found in the samples. It confirms that SARS-CoV-2 causes cell senescence.
SASP was observed not only in ciliated epithelial cells but also in macrophages. It means that virus-induced senescence is transmitted from ciliated epithelial cells to macrophages, attracted by SASP, and other types of mucosal epithelial cells that are less sensitive to the virus.
SARS-CoV-2 enters the epithelial cells of the upper respiratory tract and causes a senescence reaction in them. Senescent cells intensively secrete pro-inflammatory cytokines. Cytokines attract macrophages to the upper respiratory tract. Macrophages undergo a secondary switch to senescence and increase the secretion of pro-inflammatory cytokines. Once in the lower respiratory tract, such macrophages cause senescence of lung cells, especially endothelial cells.
The primary components of severe COVID-19 are cytokine storms and macrophage activation syndrome. The lungs of COVID-19 patients showed infiltration with pro-inflammatory macrophages.
In severe COVID-19, a strong association was observed between high serum SASP levels and increased blood clotting. There was also a strong link between SASP and microthrombosis in the lungs affected by COVID-19.
In laboratory conditions, scientists have confirmed that cell senescence under the influence of a virus causes neighboring cells, including macrophages, to age. It triggers the expression of pro-inflammatory and prothrombogenic proteins.
Senolytics May Eliminate Senescence Infected Cells and Mitigate COVID-19
Senolytics are anti-senescence drugs that trigger the death of senescent cells.
Previous evidence suggests that cells senescent by the virus can be considered a central therapeutic target for SARS-CoV-2 infection. Eliminating these cells at an early stage can mitigate the course of COVID-19.
Scientists conducted an experiment on hamsters with pneumonia infected with SARS-CoV-2. The anticancer drug Navitoclax reduced the number of senescent cells and the concentration of the vital pro-inflammatory factors SASP and reduced tissue damage. That confirms the possibility of using Navitoclax as a senolytic.
Similar effects were observed with quercetin in conjunction with dasatinib (D / Q). D / Q significantly reduced the signs of lung disease. The effects in the D/Q-treated hamsters’ group were particularly significant: all animals survived, showed no apparent signs of disease, and did not have significant weight loss. However, considerable weight loss and clinical impairment were observed in the group receiving Navitoclax.
The following experiment on mice confirmed these data. Mice infected with SARS-CoV-2 received Navitoclax, D/Q, or Fisetin. All the mice survived in the D/Q and Fisetin groups, had limited weight loss, and were asymptomatic at 6 days post-challenge. With all treatment regimens, markers of senescent cells were significantly lower in the lungs of mice treated with senolytics.
Quercetin has been tested as an oral formulation with sunflower lecithin versus standard treatment in two randomized clinical trials in patients with confirmed SARS-CoV-2 infection and mild COVID-19 symptoms (ClinicalTrials.gov identifiers NCT04578158 and NCT04861298). In studies involving 152 and 42 COVID-19 patients, quercetin contributed to clinical improvement.
A pooled analysis of all 194 patients showed that the quercetin group had a significantly lower risk of hospitalization and the need for oxygen therapy compared with standard care. The quercetin group had a lower hospital stay, ICU referrals, and deaths. Early treatment with senolytics during SARS-CoV-2 infection significantly attenuated lung disease and systemic inflammation.
Conclusions
SARS-CoV-2-induced cellular senescence increases the severity of COVID-19. Early treatment with senolytics prevents severe COVID-19. Compounds such as flavonoids, quercetin, and fisetin are desirable candidates as senolytics targeting cells senescent by the virus.
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Reference
Virus-induced senescence is a driver and therapeutic target in COVID-19
