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

Maria Belland Olsen; Camilla Huse; Mirta Mittelstedt Leal de Sousa; Sarah Louise Murphy; Antonio Sarno; Tobias Sebastian Obermann; Kuan Yang; Jan Cato Holter; Marte Jøntvedt Jørgensen; Erik Egeland Christensen; Wei Wang; Ping Ji; Lars Heggelund; Hedda Hoel; Anne Margarita Dyrhol-Riise; Ida Gregersen; Pål Aukrust; Magnar Bjørås; Bente Halvorsen; Tuva Børresdatter Dahl

doi:10.2147/JIR.S379331

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

J Inflamm Res. 2022 Dec 7:15:6629-6644. doi: 10.2147/JIR.S379331. eCollection 2022.

Authors

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 Obermann³, Kuan Yang¹, Jan Cato Holter^{2

6}, Marte Jøntvedt Jørgensen^{2

7}, Erik Egeland Christensen^{2

7}, Wei Wang³, Ping Ji³, Lars Heggelund^{8

9}, Hedda Hoel^{1

10}, Anne Margarita Dyrhol-Riise^{2

7}, Ida Gregersen¹, Pål Aukrust^{1

2

11}, Magnar Bjørås^{3

6}, Bente Halvorsen^{1

2}, Tuva Børresdatter Dahl¹²

Affiliations

¹ Research Institute of Internal Medicine, Oslo University Hospital, Oslo, Norway.
² Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
³ Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway.
⁴ Proteomics and Modomics Experimental Core Facility (PROMEC), NTNU, Trondheim, Norway.
⁵ Department of Fisheries and New Biomarine Industry, SINTEF Ocean, Trondheim, Norway.
⁶ Department of Microbiology, Oslo University Hospital and University of Oslo, Oslo, Norway.
⁷ Department of Infectious Diseases, Oslo University Hospital, Oslo, Norway.
⁸ Department of Internal Medicine, Vestre Viken Hospital Trust, Drammen, Norway.
⁹ Department of Clinical Science, Faculty of Medicine, University of Bergen, Bergen, Norway.
¹⁰ Department of Medicine, Lovisenberg Diaconal Hospital, Oslo, Norway.
¹¹ Section of Clinical Immunology and Infectious Diseases, Oslo University Hospital, Oslo, Norway.
¹² Division of Critical Care and Emergencies, Oslo University Hospital, Oslo, Norway.

Abstract

Purpose: 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; DNA damage; DNA repair; base excision repair; double strand break repair; oxidative stress.

Grants and funding

This study has received funding from the Research Council of Norway (grant no. 312780), a private donation from Vivaldi Invest A/S owned by Jon Stephenson von Tetzchner and South-Eastern Norway Regional Health Authority (Helse Sør-Øst RHF, abbreviated HSØ) funding no. 2021071.