- SARS-CoV-2 can induce cellular senescence, which exacerbates the senescence-associated secretory phenotype (SASP).
- The SASP is mainly comprised of pro-inflammatory, extracellular matrix-degrading, complement-activating, and pro-coagulatory factors secreted by senescent cells.
- Elderly individuals have an increased proportion of pre-existing senescent cells in their tissues, making them more susceptible to SASP-related tissue damage.
- SASP factors can contribute to a ‘cytokine storm’, immune cell infiltration, endothelialitis, fibrosis, and microthrombosis.
- The SASP-driven spreading of cellular senescence can amplify the SASP by increasing the burden of senescent cells, uncoupling tissue injury from direct SARS-CoV-2-inflicted cellular damage in a paracrine fashion.
- Senolytic agent (Navitoclax, fisetin, and a combination of dasatinib and quercetin) demonstrated significant cytotoxic activity against VIS cells (including human nasal epithelial cells exposed to SARS-CoV-2) in vitro, leaving uninfected or virus-infected but genetically senescence-incapable cells virtually unaffected
- Navitoclax was shown to significantly reduce extended signs of cellular senescence and SASP in SARS-CoV-2-infected mice
- Activated adventitial niches are crucial microenvironments contributing to prolonged lung immunopathology n severe COVID-19.
- Up-regulation of chemokines CCL21 and CCL18 is associated with endothelial-to-mesenchymal transition and tissue fibrosis in these niches.
- CCL21 over-expression is linked to the local accumulation of T cells expressing the cognate receptor CCR7.
- These T cells are imprinted with an exhausted phenotype and form lymphoid aggregates that can organize in ectopic lymphoid structures.
- The study proposes immune-stromal interaction mechanisms promoting a self-sustained and non-resolving local immune response that extends beyond active viral infection and perpetuates tissue remodeling.