Omicron's Cellular Senescence May Explain Cytokine Storms and Long-COVID

A new research paper was published on the cover of Aging (listed by MEDLINE/PubMed as "Aging (Albany NY)" and "Aging-US" by Web of Science) Volume 15, Issue 23, entitled, "Uncovering a unique pathogenic mechanism of SARS-CoV-2 omicron variant: selective induction of cellular senescence."

SARS-CoV-2 variants are constantly emerging with a variety of changes in the conformation of the spike protein, resulting in alterations of virus entry mechanisms. Solely omicron variants use the endosomal clathrin-mediated entry.

In this new study, researchers Franziska Hornung, Nilay Köse-Vogel, Claude Jourdan Le Saux, Antje Häder, Lea Herrmann, Luise Schulz, Lukáš Radosa, Thurid Lauf, Tim Sandhaus, Patrick Samson, Torsten Doenst, Daniel Wittschieber, Gita Mall, Bettina Löffler, and Stefanie Deinhardt-Emmer from Jena University, Leibniz Centre for Photonics in Infection Research (LPI), University of California San Francisco, Klinik für Herz- und Thoraxchirurgie, and University Hospital Bonn investigated the influence of defined altered spike formations to study their impact on premature cellular senescence.

"In our study, in vitro infections of SARS-CoV-2 variants delta (B.1.617.2) and omicron (B.1.1.529) were analyzed by using human primary small alveolar epithelial cells and human ex vivo lung slices. We confirmed cellular senescence in human lungs of COVID-19 patients. Hence, global gene expression patterns of infected human primary alveolar epithelial cells were identified via mRNA sequencing."

Solely omicron variants of SARS-CoV-2 influenced the expression of cell cycle genes, highlighted by an increased p21 expression in human primary lung cells and human ex vivo lungs. Additionally, an upregulated senescence-associated secretory phenotype (SASP) was detected. Transcriptomic data indicate an increased gene expression of p16, and p38 in omicron-infected lung cells. Significant changes due to different SARS-CoV-2 infections in human primary alveolar epithelial cells with an overall impact on premature aging could be identified. A substantially different cellular response with an upregulation of cell cycle, inflammation- and integrin-associated pathways in omicron infected cells indicates premature cellular senescence.

"This difference may be attributed to the distinct endocytic cell entry and intracellular pathways of the omicron variant when compared to the delta variant. The induction of cellular senescence in lung tissue following acute SARS-CoV-2 infection could potentially contribute to the reported cytokine storm and the development of long-COVID."