High Glucose Metabolism Fuels Cathepsin L Maturation to Promote SARS-CoV-2 Infection in Patients with Diabetes

Patients with diabetes are more likely to develop severe COVID-19 and deaths. However, the underlying mechanism remains poorly understood. Previously, we identified a widely expressed lysosome protease Cathepsin L (CTSL) promotes SARS-CoV-2 infection and may be a promising drug target (PMID: 33774649, 35668062). Here, we show that patients with diabetes have elevated CTSL concentration and activity in patients with or without COVID-19. The CTSL levels are positively correlated with HbA1c in humans. Hyperglycemic clamp study suggests that high glucose increases CTSL activity in healthy individuals. In vitro, we find that high glucose, but not high insulin, level promotes SARS-CoV-2 infection in wildtype (WT) cells. However, these promoting effects are largely reduced in CTSL-knockout (KO) cells. By using lung tissues from healthy, diabetic patients, WT and db/db mice, we find diabetes promotes CTSL maturation. Further, we identify that high glucose level, but not high insulin level, promotes CTSL activity. The matured CTSL levels are significantly increased in diabetic tissues. High glucose promotes CTSL translocation from the endoplasmic reticulum (ER) to lysosome through the ER-Golgi-lysosome axis (Fig.1). Our study reports the biological and potential clinical significance of glucose metabolism in CTSL maturation to promotes SARS-CoV-2 infection in patients with diabetes. Disclosure M.Zhao: None. Q.He: None. J.Yang: None. Funding National Natural Science Foundation of China (81930019)