Cell-free DNA tissues of origin by methylation profiling reveals significant cell, tissue, and organ-specific injury related to COVID-19 severity

Cheng, Alexandre Pellan; Cheng, Matthew P.; Lenz, Joan Sesing; Hsu, Elaine; Schurr, Erwin; Bourque, Guillaume; Bourgey, Mathieu; Ritz, Jérôme; Marty, Francisco M.; Chiu, Charles Y.; Vinh, Donald C.; Vlaminck, Iwijn De

doi:10.1016/j.medj.2021.01.001

Cited by 56 publications

(75 citation statements)

References 58 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Tissue-specific cfDNA markers correlated with known biochemical measures of end-organ injury. Some of these tissue-specific cfDNA markers demonstrated high performance to identify patients who required ICU care or who subsequently died, similar to the findings of a recent report ( 37 ). After multivariate analysis correcting for known risk factors for severe COVID-19 disease, including increasing age, male sex, and obesity, there remained a significant association of elevated risk of poor clinical outcome.…”

Section: Discussionsupporting

confidence: 85%

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

Andargie¹,

Tsuji²,

Seifuddin³

et al. 2021

JCI Insight

112

View full text Add to dashboard Cite

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. FUNDING Intramural Targeted Anti–COVID-19 grant, NIH.

show abstract

Section: Discussionsupporting

confidence: 85%

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

Andargie¹,

Tsuji²,

Seifuddin³

et al. 2021

JCI Insight

112

View full text Add to dashboard Cite

show abstract

“…In contrast to other infectious diseases that also induce autoantibodies ( Rivera-Correa & Rodriguez, 2018 ), we observed that the levels of IC are not increased in the circulation of COVID-19 patients. This is unexpected, considering the high levels of autoimmune antibodies with specificities for antigens that are likely to be accessible in the circulation, such as PS in exosomes or cell-free DNA ( Cheng et al, 2021 ). However, it is possible that IC are being formed, but are rapidly removed from the circulation, which would be consistent with the observed correlations between levels of IC and parameters indicating kidney disfunction.…”

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

“…COVID-19 patients have high levels of cell-free DNA in the circulation, which are also related to disease severity ( Lee et al, 2020 ; Cheng et al, 2021 ). Furthermore, we observed a strong correlation between markers of cell injury and anti-DNA levels, which mirrors the previously found correlation between these markers and cell-free DNA levels ( Cheng et al, 2021 ). Because the levels of cell-free DNA and anti-DNA correlate with severity of disease and markers of cell injury, it is likely that the binding of anti-DNA to cell-free DNA contributes to the pathogenesis of COVID-19 manifestations.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Autoimmune anti-DNA and anti-phosphatidylserine antibodies predict development of severe COVID-19

et al. 2021

View full text Add to dashboard Cite

High levels of autoimmune antibodies are observed in COVID-19 patients but their specific contribution to disease severity and clinical manifestations remains poorly understood. We performed a retrospective study of 115 COVID-19 hospitalized patients with different degrees of severity to analyze the generation of autoimmune antibodies to common antigens: a lysate of erythrocytes, the lipid phosphatidylserine (PS) and DNA. High levels of IgG autoantibodies against erythrocyte lysates were observed in a large percentage (up to 36%) of patients. Anti-DNA and anti-PS antibodies determined upon hospital admission correlated strongly with later development of severe disease, showing a positive predictive value of 85.7% and 92.8%, respectively. Patients with positive values for at least one of the two autoantibodies accounted for 24% of total severe cases. Statistical analysis identified strong correlations between anti-DNA antibodies and markers of cell injury, coagulation, neutrophil levels and erythrocyte size. Anti-DNA and anti-PS autoantibodies may play an important role in the pathogenesis of COVID-19 and could be developed as predictive biomarkers for disease severity and specific clinical manifestations.

show abstract

“…MN may also contribute to cfDNA when they are extruded from live cells as has been shown in live cell imaging studies in vitro but this has yet to be demonstrated in vivo [ 38 , 39 ]. Recent investigations showed that severity of COVID-19 disease and its progression is significantly associated with cfDNA in plasma, especially cfDNA identified as originating from lung, liver and erythroblasts identified using DNA methylation profiling [ 40 , 41 ]. Some of the cfDNA originates from neutrophil extracellular traps (NETs) that are released by neutrophils to destroy pathogens; it was reported that sera from patients with COVID-19 have elevated levels of myeloperoxidase-DNA complexes, and citrullinated histone H3 that are specific biomarkers of NETs [ 42 ].…”

Section: The Cellular Responses To Viral Infections and Covid-19 In Particularmentioning

confidence: 99%

Inflammatory cytokine storms severity may be fueled by interactions of micronuclei and RNA viruses such as COVID-19 virus SARS-CoV-2. A hypothesis

Kirsch‐Volders

Fenech

2021

Mutation Research/Reviews in Mutation Research

View full text Add to dashboard Cite

In this review we bring together evidence that (i) RNA viruses are a cause of chromosomal instability and micronuclei (MN), (ii) those individuals with high levels of lymphocyte MN have a weakened immune response and are more susceptible to RNA virus infection and (iii) both RNA virus infection and MN formation can induce inflammatory cytokine production. Based on these observations we propose a hypothesis that those who harbor elevated frequencies of MN within their cells are more prone to RNA virus infection and are more likely, through combined effects of leakage of self-DNA from MN and RNA from viruses, to escalate pro-inflammatory cytokine production via the cyclic GMP–AMP synthase (cGAS), stimulator of interferon genes (STING) and the Senescence Associated Secretory Phenotype (SASP) mechanisms to an extent that is unresolvable and therefore confers high risk of causing tissue damage by an excessive and overtly toxic immune response. The corollaries from this hypothesis are (i) those with abnormally high MN frequency are more prone to infection by RNA viruses; (ii) the extent of cytokine production and pro-inflammatory response to infection by RNA viruses is enhanced and possibly exceeds threshold levels that may be unresolvable in those with elevated MN levels in affected organs; (iii) reduction of MN frequency by improving nutrition and life-style factors increases resistance to RNA virus infection and moderates inflammatory cytokine production to a level that is immunologically efficacious and survivable.

show abstract

Cell-free DNA tissues of origin by methylation profiling reveals significant cell, tissue, and organ-specific injury related to COVID-19 severity

Cited by 56 publications

References 58 publications

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

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

Autoimmune anti-DNA and anti-phosphatidylserine antibodies predict development of severe COVID-19

Inflammatory cytokine storms severity may be fueled by interactions of micronuclei and RNA viruses such as COVID-19 virus SARS-CoV-2. A hypothesis

Contact Info

Product

Resources

About