Abstract
Background: Endotheliitis in severe SARS-CoV-2 (CoV2) results in increased cellular adhesion molecules (CAMs) and procoagulant molecules (PCMs). Cell surface CAMs increase endothelial cell (EC) interactions with circulating immune cells (IC). Increased EC-IC interactions and a procoagulant EC phenotype augment immunothrombotic risk during CoV2 infection. Prophylactic anticoagulants during CoV2 infection are associated with unacceptably high bleeding risk. New targets to treat endotheliitis are required. Hypothesis: We hypothesize chromatin modifying enzymes (CME)s associated with inflammatory NF-kB signaling drive transcriptional changes in endothelial cells (ECs) leading to a prothrombotic and procoagulant phenotype. Aims: Identify potential CMEs that drive CoV-2 endotheliitis. Methods: Public human single cell RNA sequencing data evaluated the pulmonary endothelial epigenetic transcriptome (PMID34876692). Murine venous ECs (mVECs), EOMA cells, and human venous ECs (HUVECs) were treated with murine beta-coronavirus (MHV-A59) or CoV2 spike protein (S1), respectively. Pharmacologic and siRNA inhibition were used to accomplish MLL1 silencing. Results: Humans with fatal CoV2 infection demonstrated marked increase in the KMT2/MLL class of histone methyltransferases in pulmonary ECs. mVEC infection significantly increased transcription of CME kmt2a, CAM esel, and PCMs plau and f3. Significant enrichment of H3K4 methylation and MLL1 are seen on promotors of identified genes. Inhibition of MLL1 reduced CAM and PCM transcripts. Functional EC-IC adhesion testing revealed significant decreases in monocyte adhesion with MLL1 inhibition. Conclusion: Kmt2a/MLL1 positively regulates CoV-2 induction of CAMs and PCMs, endothelial inflammation via positive regulation of CAM gene transcription, and resultant EC-IC interactions. MLL1 may represent a novel therapeutic target to ameliorate immunothrombotic risk during CoV-2 infection.
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