Delineating the SARS-CoV-2 Induced Interplay between the Host Immune System and the DNA Damage Response Network

Abstract

COVID-19 is an infectious disease caused by the SARS-CoV-2 coronavirus and characterized by an extremely variable disease course, ranging from asymptomatic cases to severe illness. Although all individuals may be infected by SARS-CoV-2, some people, including those of older age and/or with certain health conditions, including cardiovascular disease, diabetes, cancer, and chronic respiratory disease, are at higher risk of getting seriously ill. For cancer patients, there are both direct consequences of the COVID-19 pandemic, including that they are more likely to be infected by SARS-CoV-2 and more prone to develop severe complications, as well as indirect effects, such as delayed cancer diagnosis or treatment and deferred tests. Accumulating data suggest that aberrant SARS-CoV-2 immune response can be attributed to impaired interferon signaling, hyper-inflammation, and delayed adaptive immune responses. Interestingly, the SARS-CoV-2-induced immunological abnormalities, DNA damage induction, generation of micronuclei, and the virus-induced telomere shortening can abnormally activate the DNA damage response (DDR) network that plays a critical role in genome diversity and stability. We present a review of the current literature regarding the molecular mechanisms that are implicated in the abnormal interplay of the immune system and the DDR network, possibly contributing to some of the COVID-19 complications.

SARS-CoV-2 and the DNA damage response

“…I also consider the implications of this for the long Covid syndrome. Previous reviews have also examined the relationship between SARS-CoV-2 and the DDR [75,76]. In the latter case, emphasis has been placed on the host immune system.…”

“…It is now becoming apparent that the same is the case for many RNA viruses [43]. SARS-CoV-2 falls into that category in that viral proteins have been shown to associate with components of the DDR pathways (reviewed in [75, 76, 174]) and the virus can affect various DDR pathways such as those based on ATR and ATM signalling [136, 175].…”

Self-DNA driven inflammation in COVID-19 and after mRNA-based vaccination: lessons for non-COVID-19 pathologies

“…However, during later stages of the infection cycle, SARS-CoV-2 triggers an ongoing expression and/or activation of the transcription factor nuclear factor kappa light chain enhancer in B-cells (NF-κB) and downstream, of tumour necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, IL-18 (hereinafter termed ‘pro-inflammatory cytokines’) and IFN-γ (the only type II IFN), with little contribution of antiviral IFN I/III ( 3 , 10 ). The resulting cytokine storm ( 11 ) sustains detrimental inflammation and drives massive bystander cell death, thereby generating endothelial damage in multiple organs and – most likely – causing the progress to severe forms of COVID-19, with potentially fatal outcomes ( 3 , 7 , 10 , 12 – 16 ).…”

Efficacy of Tocilizumab in Severely Ill COVID-19 Patients With Rapid Respiratory Deterioration: A Single Center Experience During the Third Pandemic Wave in Greece

“…Tocilizumab (TCZ), a monoclonal antibody against interleukin-6 receptor-alpha (IL-6Ra), is indicated for the treatment of several inflammatory diseases, such as rheumatoid arthritis, giant cell arteritis, juvenile idiopathic arthritis, and cytokine release syndrome (4). Based on the findings that within the cytokine storm, IL-6 plays a pivotal role in COVID-19 progression and is a prognostic indicator of poor outcomes, TCZ has been the most widely evaluated therapeutic intervention for severely or critically ill patients since the pandemic onset (5,6). Despite the discordant trial outcomes regarding TCZ efficacy, ranging from significantly reduced need for mechanical ventilation, and mortality rates to evident treatment-related harm, it is now endorsed by the World Health Organization (WHO) and other regulatory bodies, such as the U.S Food and Drug Administration (FDA), the Infectious Diseases Society of America (IDSA), the National Institutes of Health (NIH), the European Medicines Agency (EMA), and several national committees as part of the standard of care (SoC) therapy for severe or critical COVID-19 (7)(8)(9)(10)(11)(12) The aim of the study was to assess the efficacy of TCZ in patients with severe COVID-19 pneumonia, and signs of rapid respiratory deterioration, during the period following after the recommendation of IL-6R blockade treatment by NIH COVID-19 Treatment Guidelines Panel until the prevalence of Omicron variant that causes significantly less morbidity (11).…”