The Epigenetic Enzyme KMT2A/MLL1 Is a Driver of Coronavirus-associated Coagulopathy

Objectives: Coronavirus associated coagulopathy (CAC) is postulated to be driven by systemic macrophage activation after SARS-CoV-2 infection and presents with elevated risk of thrombogenesis and hyperfibrinolysis. Previous work shows that the histone methyltransferase KMT2A/MLL1 is a key mediator of inflammatory signaling in monocytes and macrophages (Mo/Mϕs). In this study, we sought to identify the regulation of factors important in CAC by MLL1. Methods: Mice with myeloid specific knockout of MLL1 (Cre+) and littermate controls (Cre-) underwent intranasal inoculation of 2 x 10 5 pfu of the murine coronavirus MHVA59, an established model which phenocopies SARS-CoV-2 infection. Splenic Mϕs (surrogate for circulating Mo/Mϕs) were isolated and RNA and protein levels of urokinase (Plau; profibrinolytic), urokinase receptor (Plaur; profibrinolytic), and tissue factor (F3/TF; procoagulant) were analyzed using qRT-PCR and ELISA, respectively. Thromboelastography (TEG) on whole blood and urokinase activity assays from mouse plasma were performed. Urokinase and TF activity assays were performed on plasma from human samples. Results: RNA (top panel) and protein (bottom) levels of Plau, Plaur, and F3 were suppressed in the Splenic Mϕs harvested from sham (intranasal PBS) and infected Cre+ animals (white bars) compared to Splenic Mϕs harvested from Cre- animals (blue bars; Fig. 1A). Cre- mice displayed a shortened R-time (reaction time) as measured by TEG (Fig. 1B) and elevated plasma urokinase activity levels (not shown). Hospitalized COVID-positive patients (hCOV+) displayed elevated plasma urokinase and TF activity levels (Fig. 1C). Conclusions: We identify a role for MLL1 for basal expression and for coronavirus-mediated induction of factors important for fibrinolysis and coagulation in murine Mo/Mϕs and in driving coagulopathy. Our results suggest that MLL1 blockade may be an attractive strategy to combat coronavirus associated coagulopathy.