The Histone Methyltransferase MLL1/KMT2A in Monocytes Drives Coronavirus-Associated Coagulopathy and Inflammation.

Coronavirus-associated coagulopathy (CAC) is a morbid and lethal sequela of SARS-CoV-2 infection. CAC results from a perturbed balance between coagulation and fibrinolysis and occurs in conjunction with exaggerated activation of monocytes/macrophages (MO/Mφs) and the mechanisms that collectively govern this phenotype seen in CAC remain unclear. In this study, using experimental models that employ the murine betacoronavirus MHVA59, a well-established model of SARS-CoV-2 infection, we identify that the histone methyltransferase Mixed Lineage Leukemia 1 (MLL1/KMT2A) is an important regulator of MO/Mφ expression of procoagulant and profibrinolytic factors such as tissue factor (F3; TF), urokinase (PLAU), and urokinase receptor (PLAUR) (herein "coagulopathy-related factors") in non-infected and infected cells. We show that MLL1 concurrently promotes the expression of the proinflammatory cytokines while suppressing the expression of interferon a (IFNa), a well-known inducer of TF and PLAUR. Using in vitro models, we identify MLL1-dependent NFκB/RelA-mediated transcription of these coagulation-related factors and identify a context dependent MLL1-independent role for RelA in the expression of these factors in vivo. As functional correlates for these findings, we demonstrate that the inflammatory, procoagulant and profibrinolytic phenotypes seen in vivo after coronavirus infection were MLL1-dependent despite blunted Ifna induction in MO/Mφs. Finally, in an analysis of SARS-CoV-2 positive human samples, we identify differential upregulation of MLL1 and coagulopathy-related factor expression and activity in CD14+ MO/Mφs relative to non-infected and healthy controls. We also observed elevated plasma urokinase and TF activity in COVID-positive samples. Collectively, these findings highlight an important role for MO/Mφ MLL1 in promoting coronavirus-associated coagulopathy and inflammation.