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

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.

SARS-CoV-2 and the DNA damage response

“…Increased levels of oxidized guanine were generally observed in COVID-19 patients with much higher levels in those with more severe disease. In a second study, perhaps surprisingly, similar levels of 8-oxo-G were observed in peripheral blood mononuclear cells (PBMCs) from healthy and SARS-CoV-2-infected individuals [172]. However, elevated levels of some, but not all, base excision repair proteins (for example, POLD1, MPG, ligase 1 and FEN1) and double-strand break repair proteins (for example, Chk1, RAD50 and RAD51) were reported in COVID-19 patients [172].…”

“…In a second study, perhaps surprisingly, similar levels of 8-oxo-G were observed in peripheral blood mononuclear cells (PBMCs) from healthy and SARS-CoV-2-infected individuals [172]. However, elevated levels of some, but not all, base excision repair proteins (for example, POLD1, MPG, ligase 1 and FEN1) and double-strand break repair proteins (for example, Chk1, RAD50 and RAD51) were reported in COVID-19 patients [172]. In addition, it was noted that more highly regulated DDR pathway protein expression was correlated with severity of disease.…”