ABSTRACT
The COVID-19 pandemic has revealed the pronounced vulnerability of the elderly and chronically ill to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-induced morbidity and mortality. Cellular senescence contributes to inflammation, multiple chronic diseases, and age-related dysfunction, but effects on responses to viral infection are unclear. Here, we demonstrate that senescent cells (SnCs) become hyper-inflammatory in response to pathogen-associated molecular patterns (PAMPs), including SARS-CoV-2 spike protein-1, increasing expression of viral entry proteins and reducing antiviral gene expression in non-SnCs through a paracrine mechanism. Old mice acutely infected with pathogens that included a SARS-CoV-2-related mouse ß-coronavirus experienced increased senescence and inflammation, with nearly 100% mortality. Targeting SnCs by using senolytic drugs before or after pathogen exposure significantly reduced mortality, cellular senescence, and inflammatory markers and increased antiviral antibodies. Thus, reducing the SnC burden in diseased or aged individuals should enhance resilience and reduce mortality after viral infection, including that of SARS-CoV-2.
Subject(s)
Aging , Cellular Senescence/drug effects , Coronavirus Infections/mortality , Flavonols/therapeutic use , Pathogen-Associated Molecular Pattern Molecules/metabolism , Spike Glycoprotein, Coronavirus/metabolism , Animals , COVID-19/immunology , COVID-19/mortality , Cell Line , Coronavirus Infections/immunology , Dasatinib/pharmacology , Dasatinib/therapeutic use , Female , Flavonols/pharmacology , Gene Expression Regulation , Humans , Lipopolysaccharides , Male , Mice , Mice, Inbred C57BL , Murine hepatitis virus/immunology , Quercetin/pharmacology , Quercetin/therapeutic use , Receptors, Coronavirus/genetics , Receptors, Coronavirus/metabolism , Specific Pathogen-Free Organisms , COVID-19 Drug TreatmentABSTRACT
As the SARS-CoV-2 pandemic has progressed, increasing attention has focused on establishing natural and vaccine-induced immunity against this coronavirus and the disease, COVID-19, that it causes. In this Primer, we explain the fundamental features of T cell memory and their potential relevance for effective immunity to SARS-CoV-2.