Fig. 2: A mechanistic working model of senescence-driven severe COVID-19.

The infection of susceptible respiratory mucosa cells in the upper airways with SARS-CoV-2 evokes virus-induced senescence (VIS). Like pre-existing, ageing-associated and chronic disease-associated senescent cells, they release large amounts of largely pro-inflammatory cytokines and other senescence-associated secretory phenotype (SASP) factors (see Fig. 1). Macrophages that are attracted to senescent cells via cytokines and chemokines (such as macrophage colony-stimulating factor (M-CSF) or CCL2 (ref.²⁸)) can acquire a senescence-like condition via paracrine SASP action. These macrophages amplify the production of SASP factors and serve as ‘mobile messengers’ that provide a broad spectrum of SASP factors to more distal airways. Together with the direct viral infection of cells in the lower respiratory tract and an enhanced burden of senescent cells due to paracrine, SASP-mediated induction of secondary senescence, macrophages and other SASP-producing cells collectively promote lung pathology by contributing to local tissue damage. This is partly due to SASP-mediated cytotoxicity and partly via direct macrophage phagocytosis of infected or otherwise altered cells. Moreover, SASP factors attract other immune cells and excessive activation of these cells can result in direct or indirect cytotoxicity at lung epithelial and endothelial cells. Specifically, VIS-driven features of severe, tissue-destructive coronavirus disease 2019 (COVID-19) include endothelial cell senescence, complement-mediated cytolysis of endothelial cells, neutrophil extracellular trap (NET) formation, platelet activation and microthrombosis and, presumably, SASP-enhanced T cell-mediated cytotoxicity towards alveolar epithelial cells (AECs) I and II. Pre-existing senescent, virus-induced senescent and secondary SASP-induced senescent cells are depicted in blue. See main text for details.