Viral-specific induction of cellular and soluble urokinase plasminogen activator receptor (suPAR) expression

Urokinase (uPA) and urokinase plasminogen activator receptor (uPAR/PLAUR) mediate fibrinolysis and matrix remodeling. Liberation of monocyte/macrophage (MO/Mφ)-bound soluble uPAR (suPAR) occurs after infection with coronaviruses (CoVs) such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), correlating with systemic inflammatory stress and end-organ injury severity. How suPAR liberation from MO/Mφs occurs after CoV infection, and whether suPAR induction is exclusive to coronavirus infection or occurs from other clinically significant coagulopathy-inducing pneumotropic viral infections such as influenza A (IAV), is unknown. We noted increased PLAUR transcripts in peripheral blood mononuclear cells (PBMCs) from SARS-CoV-2-positive and IAV-positive patients. Elevated suPAR liberation was observed after murine CoV infection but not IAV infection-both of which led to increased MO/Mφ mRNA and cell-bound uPA and uPAR, and increased secreted uPA activity. uPA knockdown in MO/Mφs abrogated suPAR liberation and blunted tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6 induction post-CoV, suggesting that targeting co-regulators of uPAR and uPA may be beneficial in attenuating coronavirus-driven inflammatory cytokine responses, and treating diseases characterized by suPAR release from Mφs.