Written by Charlotte Harrison, Science Writer
A study of a small number of patients hospitalized with severe COVID-19 shows that, at the time of hospital admission, when patients had equal disease severity, there were differences in the epigenetic and transcriptomic profile of monocytes between patients who would survive and those who would not survive.
The study, published in Science Advances, followed seven critically ill patients at admission and 5 and 15 days after admission. Single-cell RNA sequencing was used to understand the cellular composition and transcriptional status of immune cells — including B cells, myeloid cells, and natural killer cells — between the three patients that died and four who recovered.
Transcriptional and epigenetic changes
The authors found that monocytes played a key role in the earlier stages of disease (at the time of admission). In particular, there were transcriptional changes in molecular pathways associated with epigenetic changes in this cell type. However, the monocyte transcriptome had only a modest impact on prognosis at later stages of disease; here, disease evolution was characterized by changes in the composition of cells.
The authors next investigated the chromatin accessibility of monocytes using ATAC sequencing. Overall, the epigenetic profile of monocytes correlated with poor prognosis. This result adds to the growing number of studies showing that monocytes have a pivotal role in COVID-19 severity and prognosis.
Biological mechanisms and drug targets
To understand the biological mechanisms underlying the epigenetic differences in monocytes, the authors performed DNA binding motif enrichment for differential accessible chromatin regions at the time of hospital admission. In patients who died, there was a higher proportion of less-accessible chromatin regions than more-accessible chromatin regions. This part of the study found motifs for transcription factors with Sp1-like and E2F-like binding motifs. These transcription factors are involved in the cell cycle, differentiation and chromatin remodelling, as well as immune responses.
Finally, to identify potential new drugs and targets, the authors performed an ingenuity pathway analysis of differentially expressed genes that were associated with poor prognosis. This analysis identified pathways linked to messenger RNA metabolism, RNA splicing and interferon signalling that were overactivated in patients who would not survive.
Several candidate drugs were identified, including dexamethasone (which is currently used for treating severe disease) as well as numerous other drugs that might, following further studies, be repurposed for COVID-19. These drugs included the immunosuppressant tacrolimus, zotatifin (an inhibitor of eIF4A1-mediated translation) and the tyrosine kinase inhibitor nintedanib.