Mixed-lineage leukemia 1 (Kmt2a/MLL1) as a central mediator of endothelial inflammation in SARS-CoV-2 infection

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Presentation Time: 03:15 PM - 04:30 PM
Poster Board Number: B232
Abstract ID: 4581

Presenting Author:
Nathaniel Parchment , Resident Physician at Michigan Med., Univ. of Michigan

Abstract:

Background: The endothelial cell (EC) inflammatory response during severe SARS-CoV-2 (CoV2) results in increased circulating cellular adhesion molecules (CAMs) with subsequent leukocyte infiltrate, immunothrombosis, and end organ dysfunction. The underlying mechanism of CAM induction is incompletely understood.

Methods: Pulmonary endothelial epigenetic transcriptome was analyzed from publicly available human single cell RNA sequencing data (PMID34876692). Murine venous ECs (mVECs), C57Bl6 mice, and human venous ECs (HUVECs) were treated with murine beta-coronavirus (MHV-A59) and CoV2 spike protein (S1), respectively. MLL1 silencing was accomplished via small interfering RNA (siRNA) transfection or pharmacologic inhibition.

Results: Amongst humans with fatal CoV2, histone methyltransferase kmt2a/MLL1 was significantly elevated in pulmonary ECs. Mice harvested 7 days post infection had increased circulating E-selectin and albumin in bronchoalveolar lavage, suggesting endothelial inflammation and resultant barrier dysfunction. mVEC infection significantly increased kmt2a, esel, icam1, and vcam1 transcription. H3K4 methylation and MLL1 were enriched on promotor regions of identified CAMs. MLL1 silencing reduced CAM transcription and abrogated virally-induced endothelial-monocyte adhesion.

Conclusion: Kmt2a/MLL1 acts as a central regulator of CoV-2 induced endothelial inflammation via positive regulation of CAM gene transcription and resultant EC-immune cell interactions.