DNA Repair Mechanisms are Activated in Circulating Lymphocytes of Hospitalized Covid-19 Patients

Abstract

Maria Belland Olsen,1,2 Camilla Huse,1,2 Mirta Mittelstedt Leal de Sousa,3,4 Sarah Louise Murphy,1,2 Antonio Sarno,3,5 Tobias Sebastian Obermann,3 Kuan Yang,1 Jan Cato Holter,2,6 Marte Jøntvedt Jørgensen,2,7 Erik Egeland Christensen,2,7 Wei Wang,3 Ping Ji,3 Lars Heggelund,8,9 Hedda Hoel,1,10 Anne Margarita Dyrhol-Riise,2,7 Ida Gregersen,1 Pål Aukrust,1,2,11 Magnar Bjørås,3,6 Bente Halvorsen,1,2 Tuva Børresdatter Dahl12 1Research Institute of Internal Medicine, Oslo University Hospital, Oslo, Norway; 2Institute of Clinical Medicine, University of Oslo, Oslo, Norway; 3Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway; 4Proteomics and Modomics Experimental Core Facility (PROMEC), NTNU, Trondheim, Norway; 5Department of Fisheries and New Biomarine Industry, SINTEF Ocean, Trondheim, Norway; 6Department of Microbiology, Oslo University Hospital and University of Oslo, Oslo, Norway; 7Department of Infectious Diseases, Oslo University Hospital, Oslo, Norway; 8Department of Internal Medicine, Vestre Viken Hospital Trust, Drammen, Norway; 9Department of Clinical Science, Faculty of Medicine, University of Bergen, Bergen, Norway; 10Department of Medicine, Lovisenberg Diaconal Hospital, Oslo, Norway; 11Section of Clinical Immunology and Infectious Diseases, Oslo University Hospital, Oslo, Norway; 12Division of Critical Care and Emergencies, Oslo University Hospital, Oslo, NorwayCorrespondence: Tuva Børresdatter Dahl, Division of Critical Care and Emergencies and Research Institute of Internal Medicine, Oslo University Hospital, Sognsvannsveien 20, Oslo, Norway, Tel [phone], Email [email protected]: Reactive oxygen species (ROS) are an important part of the inflammatory response during infection but can also promote DNA damage. Due to the sustained inflammation in severe Covid-19, we hypothesized that hospitalized Covid-19 patients would be characterized by increased levels of oxidative DNA damage and dysregulation of the DNA repair machinery.Patients and Methods: Levels of the oxidative DNA lesion 8-oxoG and levels of base excision repair (BER) proteins were measured in peripheral blood mononuclear cells (PBMC) from patients (8-oxoG, n = 22; BER, n = 17) and healthy controls (n = 10) (Cohort 1). Gene expression related to DNA repair was investigated in two independent cohorts of hospitalized Covid-19 patients (Cohort 1; 15 patents and 5 controls, Cohort 2; 15 patients and 6 controls), and by publicly available datasets.Results: Patients and healthy controls showed comparable amounts of oxidative DNA damage as assessed by 8-oxoG while levels of several BER proteins were increased in Covid-19 patients, indicating enhanced DNA repair in acute Covid-19 disease. Furthermore, gene expression analysis demonstrated regulation of genes involved in BER and double strand break repair (DSBR) in PBMC of Covid-19 patients and expression level of several DSBR genes correlated with the degree of respiratory failure. Finally, by re-analyzing publicly available data, we found that the pathway Hallmark DNA repair was significantly more regulated in circulating immune cells during Covid-19 compared to influenza virus infection, bacterial pneumonia or acute respiratory infection due to seasonal coronavirus.Conclusion: Although beneficial by protecting against DNA damage, long-term activation of the DNA repair machinery could also contribute to persistent inflammation, potentially through mechanisms such as the induction of cellular senescence. However, further studies that also include measurements of additional markers of DNA damage are required to determine the role and precise molecular mechanisms for DNA repair in SARS-CoV-2 infection.Keywords: Covid-19, oxidative stress, DNA damage, DNA repair, base excision repair, double strand break repair

Keywords

• covid-19
• oxidative stress
• dna damage
• dna repair
• base excision repair
• double strand break repair.