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 - Funding Information:
This research was supported (in part) by the Intramural Research Program of the NIH through the Intramural Targeted Anti–COVID-19 grant, NHLBI, and NIDDK. SAE also received support through the NIH-Lasker Clinical Research Program, NIH Distinguished Scholar Program, and Cystic Fibrosis Foundation (grant no. AGBORE20Q10). The authors thank Jeff M. Reece for setup and advice on confocal microscopy. COVID-19 specimens utilized for this publication were part of biorepositories established at Johns Hopkins Hospital, University of Maryland Medical Center, and Inova Fairfax Hospital. The authors appreciate the dedicated contributions of the many patients, research teams, and clinicians at Johns Hopkins, who contributed to creating the biorepository; the University of Maryland Medical Center ECMO consortium; and the University of Maryland Medical Center COVID-19 group. We thank Wayne Pareanu for editorial support. This research was supported (in part) by the Intramural Research Program of the NIH through the Intramural Targeted Anti–COVID-19 grant, NHLBI, and NIDDK. Dr. Agbor-Enoh also received support through the NIH-Lask-er Clinical Research Program, NIH Distinguished Scholar Program, and Cystic Fibrosis Foundation (grant AGBORE20Q10). SAE receives funding from the Cystic Fibrosis Foundation.
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 -