Cell-free DNA maps COVID-19 tissue injury and risk of death, and can cause tissue injury.

INTRODUCTION: Coronavirus 2019 (COVID-19) clinical course is heterogeneous, ranging from mild to severe multi-organ failure and death. In this study, we analyzed cell-free DNA (cfDNA) as a biomarker of injury to define the sources of tissue injury that contribute to such different trajectories. METHODS: We conducted a multi-center prospective cohort study to enroll COVID-19 patients and collect plasma samples. Plasma cfDNA was subject to bisulfite sequencing. A library of tissue-specific DNA methylation signatures was used to analyze sequence reads to quantitate cfDNA from different tissue types. We then determined the correlation of tissue-specific cfDNA measures to COVID-19 outcomes. Similar analyses was performed for healthy controls and a comparator group of patients with respiratory syncytial virus and influenza. RESULTS: We found markedly elevated levels and divergent tissue sources of cfDNA in COVID-19 patients compared to influenza and respiratory syncytial virus patients or healthy controls. The major sources of cfDNA in COVID-19 were hematopoietic cells, vascular endothelium, hepatocyte, adipocyte, kidney, heart and lung. cfDNA levels positively correlated with COVID-19 disease severity, c reactive protein, D-Dimer. cfDNA profile at admission identified patients who subsequently required intensive care or died during hospitalization. Furthermore, the increased cfDNA in COVID-19 patients generates excessive mitochondrial reactive oxygen species (mtROS) in renal tubular cells in a concentration-dependent manner. This mtROS production was inhibited by a toll-like receptor 9 (TLR-9)-specific antagonist.Conclusion cfDNA maps tissue injury that predict COVID-19 outcomes, and may mechanistically propagates COVID-19 induced tissue injury. FUNDING SOURCES: Intramural Targeted Anti-COVID-19 grant, National Institutes of Health.