TY - JOUR
T1 - Cell-free DNA maps COVID-19 tissue injury and risk of death and can cause tissue injury
AU - Andargie, Temesgen E.
AU - Tsuji, Naoko
AU - Seifuddin, Fayaz
AU - Jang, Moon Kyoo
AU - Yuen, Peter S.T.
AU - Kong, Hyesik
AU - Tunc, Ilker
AU - Singh, Komudi
AU - Charya, Ananth
AU - Wilkins, Kenneth
AU - Nathan, Steven
AU - Cox, Andrea
AU - Pirooznia, Mehdi
AU - Star, Robert A.
AU - Agbor-Enoh, Sean
N1 - Publisher Copyright:
© 2021, Andargie et al.
PY - 2021/4/8
Y1 - 2021/4/8
N2 - INTRODUCTION. The clinical course of coronavirus 2019 (COVID-19) is heterogeneous, ranging from mild to severe multiorgan 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 multicenter prospective cohort study to enroll patients with COVID-19 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 were 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 with patients who had influenza and/or respiratory syncytial virus and with healthy controls. The major sources of cfDNA in COVID-19 were hematopoietic cells, vascular endothelium, hepatocytes, adipocytes, kidney, heart, and lung. cfDNA levels positively correlated with COVID-19 disease severity, C-reactive protein, and 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 generated excessive mitochondrial ROS (mtROS) in renal tubular cells in a concentration-dependent manner. This mtROS production was inhibited by a TLR9- specific antagonist. CONCLUSION. cfDNA maps tissue injury that predicts COVID-19 outcomes and may mechanistically propagate COVID-19-induced tissue injury.
AB - INTRODUCTION. The clinical course of coronavirus 2019 (COVID-19) is heterogeneous, ranging from mild to severe multiorgan 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 multicenter prospective cohort study to enroll patients with COVID-19 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 were 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 with patients who had influenza and/or respiratory syncytial virus and with healthy controls. The major sources of cfDNA in COVID-19 were hematopoietic cells, vascular endothelium, hepatocytes, adipocytes, kidney, heart, and lung. cfDNA levels positively correlated with COVID-19 disease severity, C-reactive protein, and 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 generated excessive mitochondrial ROS (mtROS) in renal tubular cells in a concentration-dependent manner. This mtROS production was inhibited by a TLR9- specific antagonist. CONCLUSION. cfDNA maps tissue injury that predicts COVID-19 outcomes and may mechanistically propagate COVID-19-induced tissue injury.
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U2 - 10.1172/jci.insight.147610
DO - 10.1172/jci.insight.147610
M3 - Article
C2 - 33651717
AN - SCOPUS:85104160068
SN - 2379-3708
VL - 6
JO - JCI Insight
JF - JCI Insight
IS - 7
M1 - e147610
ER -