Does Cellular Senescence Play a Role in Severe COVID-19?

Alveolar type 2 (AT2) cells infected with SARS-CoV-2 demonstrated senescence and a proinflammatory phenotype. These and other findings were presented in a preclinical study published in the European Respiratory Journal.

Investigators assessed autopsy lung tissue samples from 11 patients who had COVID-19 and similar samples from 43 health individuals who were age-matched and exhibited similar comorbidities to the COVID-19 cohort. These samples were tested for SARS-CoV-2, senescence biomarkers and key SASP cytokines. The researchers induced viral senescence in vitro via the infection of epithelial Vero-E6 cells and a 3-dimensional alveosphere system of AT2 cells with SARS-CoV-2 strains collected from COVID-19 patients.

SARS-CoV-2 was noted via immunocytochemistry and electron microscopy mostly in AT2 cells. Infected AT2 cells demonstrated angiotensin-converting-enzyme 2 (ACE2) and p16INK4A and SenTraGorTM positivity, which indicated senescence, as well as IL-1β and IL-6 expression. The in vitro infection of Vero-E6 cells with SARS-CoV-2 triggered senescence (ie, SenTraGorTM), DNA damage (ie, γ-H2AX) and increased cytokine (ie, L-1β, IL-6, CXCL8), as well as apolipoprotein B mRNA-editing (APOBEC) enzyme expression. Next-generation-sequencing analysis of progenies isolated from infected/senescent Vero-E6 cells exhibited APOBEC-mediated SARS-CoV-2 mutations. The investigators confirmed the spread of SARS-CoV-2-infection and senescence in the kidney and liver of a COVID-19 patient.

The authors suggest that SARS-CoV-2 induced senescence bulwarks the administration of senotherapeutics for the treatment of COVID-19, as well as long-COVID syndromes. Notably, quercetin was compared with standard care in 2 randomized clinical trials

One limitation of the current study is the small sample size, despite it being the largest clinical study to date exhibiting virally induced senescence by SARS-CoV-2. Of note, the autopsied tissue was hard to attain, and collected during the early phase of the pandemic.

A second limitation of the study was that pathological features including cellular senescence in lungs are only able to be assessed in cadavers. This outcome is the worst of COVID-19 clinical manifestations.

“We demonstrate that in severe COVID-19, AT2 cells infected by SARS-CoV-2 exhibit senescence and a proinflammatory phenotype,” concluded the authors. “In vitro, SARS-CoV-2 infection induces senescence and inflammation. Importantly, infected senescent cells may act as a source of SARS-CoV-2 mutagenesis mediated by APOBEC enzymes. Therefore, SARS-CoV-2-induced senescence may be an important molecular mechanism of severe COVID-19, disease persistence and mutagenesis.”

Reference

 Evangelou K, Veroutis D, Paschalaki K, et al. Pulmonary infection by SARS-COV-2 induces senescence accompanied by an inflammatory phenotype in severe COVID-19: Possible implications for viral mutagenesis. Eur Respir J. Published online February 3, 2022. doi:10.1183/13993003.02951-2021