Review 2: "Epigenetic Liquid Biopsies Reveal Elevated Vascular Endothelial Cell Turnover and Erythropoiesis in Asymptomatic COVID-19 Patients"

Shampa Chatterjee

doi:doi:10.1162/2e3983f5.3d75e1df

Epigenetic liquid biopsies reveal elevated vascular endothelial cell turnover and erythropoiesis in asymptomatic COVID-19 patients

by Roni Ben-Ami, Netanel Loyfer, Eden Cohen, Gavriel Fialkoff, Israa Sharkia, Naama Bogot, Danit Kochan, George Kalak, Amir Jarjoui, Chen Chen-Shuali, Hava Azulai, Hezi Barhoum, Nissim Arish, Moshe M Greenberger, David Vellema, Ramzi Kurd, Eli Ben Chetrit, Davina Bohm, Talya Wolak, Ahmad Quteineh, Gordon Cann, Benjamin Glaser, Nir Friedman, Tommy Kaplan, Ruth Shemer, Ariel Rokach, and Yuval Dor

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Published on Aug 01, 2023
www.biorxiv.org

Description

The full spectrum of tissues affected by SARS-CoV-2 infection is crucial for deciphering the heterogenous clinical course of COVID-19. Here, we analyzed DNA methylation and histone modification patterns in circulating chromatin to assess cell type-specific turnover in severe and asymptomatic COVID-19 patients, in relation to clinical outcome. Patients with severe COVID-19 had a massive elevation of circulating cell-free DNA (cfDNA) levels, which originated in lung epithelial cells, cardiomyocytes, vascular endothelial cells and erythroblasts, suggesting increased cell death or turnover in these tissues. The immune response to infection was reflected by elevated B cell and monocyte/macrophage cfDNA levels, and by evidence of an interferon response in cells prior to cfDNA release. Strikingly, monocyte/macrophage cfDNA levels (but not monocyte counts), as well as lung epithelium cfDNA and vascular endothelial cfDNA, predicted clinical deterioration and duration of hospitalization. Asymptomatic patients had elevated levels of immune-derived cfDNA but did not show evidence of pulmonary or cardiac damage. Surprisingly, these patients showed elevated levels of vascular endothelial cell and erythroblast cfDNA, suggesting that sub-clinical vascular and erythrocyte turnover are universal features of COVID-19, independent of disease severity. Epigenetic liquid biopsies provide non-invasive means of monitoring COVID-19 patients, and reveal sub-clinical vascular damage and red blood cell turnover.

RR:C19 Evidence Scale rating by reviewer:

Strong. The main study claims are very well-justified by the data and analytic methods used. There is little room for doubt that the study produced has very similar results and conclusions as compared with the hypothetical ideal study. The study’s main claims should be considered conclusive and actionable without reservation.

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Review: This manuscript employs liquid biopsies to monitor cell type-specific turnover in COVID-19 subjects categorized as severe and asymptomatic, and correlate it to clinical outcome. The authors analyze circulating cell-free DNA in blood of COVID-19 patients for their tissue origins and report elevation in the fraction of cfDNA from various sources viz. liver, T-cells, B-cells, lungs, vascular endothelial cells etc. They also observe elevation of vascular endothelial cfDNA indicating that vascular turnover is high even in less severe COVID cases. Finally, the authors show that the cfDNA data (i.e., its tissue/cell source) was positively and significantly correlated to disease severity.

Overall, this is a timely study in the light of the current long COVID-19 epidemic.

However, as COVD-19 has also been considered as a vascular endothelial disease, it would be worthwhile to obtain data from the subset of COVID-19 cases that were fatal. Of the severe COVID-19 samples studied, were there cases that went on to be fatal? If yes, could the correlation studies be done exclusively on those (and compared with asymptomatic and non-fatal) and added as a separate figure.

As long COVID-19 rages on after the virus is long gone, it is important to understand the role of cells and cellular processes that remain active after COVID-19. For this, information on cellular events that occur in asymptomatic patients is needed as it may guide us in detecting deleterious processes that exist after the infection is gone.

Review 2: "Epigenetic Liquid Biopsies Reveal Elevated Vascular Endothelial Cell Turnover and Erythropoiesis in Asymptomatic COVID-19 Patients"

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