The role of senescence in severe COVID-19

ABSTRACT Preexisting obesity and non alcoholic steatohepatitis (NASH) are strongly associated with COVID- 19 cytokine storm and severe outcome. SARS-CoV-2 virions are present in the patient adipose tissue and liver at low levels and it is not known if they play a major functional role in severe COVID-19 pathology. The Raabe lab has derived for the first time organoids from livers of patients

with NASH and shown that they are senescent and exhibit a senescence associated secretory phenotype (SASP) and thus model the known senescence of hepatocytes and other liver cells in end stage NASH liver. Further, SARS-CoV-2 has been shown recently to induce senescence and an SASP in infected lung cells that spreads through senescence associated secretion of

chemokines and cytokines including chemokine CXCL10, interferon IFN and cytokine TNF to attract macrophages and activate them to a pro inflammatory state. The Raabe lab will study the hypothesis that genetic or chemical removal of senescent cells in SARS-CoV-2 infected obesity or NASH mouse models or in human adipose tissues derived cells and NASH patient liver derived

organoids will alleviate NASH related severe COVID-19 symptoms. In Aim 1 we will induce obesity and NASH senescence in mouse models and infect these with SARS-CoV-2. Prior or after infection we will remove senescence promoting factor p16 expressing cells either genetically or chemically and then determine if this alleviates severe obesity or NASH COVID-19 symptoms.

In Aim 2 primary human lung cells will be infected with SARS-CoV-2 and the supernatant containing the SASP and virus will be added to primary human adipocytes or NASH liver derived organoid cultures. We will remove senescent cells chemically using established senolytics to study if their removal alleviates inflammatory responses. Readout will be RNA-Seq, IHC and

ELISA to study the effect on senolytics on the SASP.