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3948 Spatiotemporal Impact of Sars-Cov-2 Infection on the Transcriptome of Bone Marrow Megakaryocytes

Program: Oral and Poster Abstracts
Session: 301. Vasculature, Endothelium, Thrombosis and Platelets: Basic and Translational: Poster III
Hematology Disease Topics & Pathways:
Research, Fundamental Science, Viral, Translational Research, genomics, Diseases, Immune Disorders, SARS-CoV-2/COVID-19, Infectious Diseases, immunology, Biological Processes, pathogenesis
Monday, December 11, 2023, 6:00 PM-8:00 PM

Isabelle Allaeys, PhD1*, Mickael Leclercq2*, Julia Tilburg, PhD3, Andrew Stone, PhD4, Maude Fleury2*, Emile Lacasse5*, Kellie Machlus, PhD6*, Arnaud Droit1*, Louis Flamand, PhD7* and Eric Boilard, PhD1

1Centre de recherche du CHU de Québec-Université Laval, Quebec, QC, Canada
2CHU de Quebec-Universite Laval, Quebec, Canada
3Harvard Medical School, Boston, MA
4Boston Childrens Hospital, Boston, MA
5Centre de recherche du CHU de Québec-Université Laval, Quebec, Quebec, CAN
6Boston Children's Hospital, Arlington, MA
7CHU de Quebec- Universite Laval, Quebec, Canada

Megakaryocytes, integral to platelet production, predominantly reside in the bone marrow, undergoing regulated fragmentation within sinusoid vessels to release platelets into the bloodstream. Inflammatory states and infections have been shown to influence megakaryocyte transcription, potentially affecting platelet functionality. Notably, COVID-19 has been associated with altered platelet transcriptome. In this study, we hypothesized that SARS-CoV-2 infection could impact the transcriptome of bone marrow megakaryocytes, particularly those in direct proximity to the blood. Utilizing spatial transcriptomic analysis and machine learning techniques, we observed that the transcriptome of healthy mouse bone marrow megakaryocytes exhibited minimal alteration based on proximity to sinusoid vessels. Similar findings were observed during peak SARS-CoV-2 viremia, when the disease primarily affected the lungs. Conversely, a significant divergence in the transcriptome of megakaryocytes was observed during systemic inflammation, even when SARS-CoV-2 was no longer detectable in the lungs or bone marrow. Under these conditions, the transcriptional landscape was enriched in genes associated with structural and translational activities, platelet degranulation, netosis, and auto-immunity. Of the approximately ~19,000 genes identified in megakaryocytes during systemic inflammation, machine learning pinpointed 30 genes significantly altered in cells closely adjacent to sinusoid vessels, with gene ontology attributing these changes primarily to protein deSUMOylation. Intriguingly, the type-I interferon signature and calprotectin (S100A8/A9) were not induced under any condition. Inflammatory cytokines were elevated in the blood of COVID-19 mice, but not in bone marrow plasma, suggesting a preferential impact of inflammation on this specific subset of cells. Collectively, our data indicate that distinct subpopulations of bone marrow megakaryocytes may emerge based on spatial localization and the stage of COVID-19 pathogenesis.

Disclosures: No relevant conflicts of interest to declare.

*signifies non-member of ASH