A new study led by researchers from the University of Queensland-Australia involving transcriptomic profiling of cardiac tissues from SARS-CoV-2 patients identified DNA damage.
The study findings were published in the peer reviewed journal: Immunology
Pandemic H1N1 influenza drives a cytokine storm of generalized inflammation disrupting the heart which presents with fever, tachycardia, and arrhythmias.
In contrast, COVID-19 drives a now recognized syndrome which can result in acute myocardial infarction, myocardial injury, heart failure, disseminated thrombosis, hypotension, arrhythmias and sudden cardiac death .
In COVID-19 patients with adverse outcomes, cardiac troponin I and brain-type natriuretic peptide are elevated in ICU admission patients .
However, while biomarker changes are indicative of tissue damage, the mechanisms involved in cardiac injury have not been fully established. Recent studies have shown that myocarditis is prevalent in COVID-19, however, evidence for subclinical cardiac inflammation or mechanisms regulating this process has been limited.
In influenza, viral binding to host cells induces a type I and III IFN response, including inflammatory cytokines (IL-6 and TNF-α) and chemokines. The binding of the type I and III IFNs to their receptors results in activation of the JAK/STAT pathways for the induction of ISGs such as IFI27.
This can lead to acute myocarditis, a common complication of influenza infection . In contrast to influenza infection, induction of these pathways in COVID-19 is low , a feature supported by recent autopsy studies in which virus was not detected as a cause of myocarditis .
It was previously observed that excessive signalling induced by type 1 IFN induces inflammation-driven myocardial infarction and this can be triggered by self-DNA release and activation of the cGAS–STING–IRF3 pathway. This pathway is also connected to inflammation-induced DNA damage, which was suggested by others and by our current dataset .
DNA damage response and repair mechanisms have been involved in the pathogenesis of chronic conditions such as diabetes and cardiovascular disease .
However, the role of SARS-CoV-2 in inducing genome instability has not been fully ascertained. In vitro studies have shown that the SARS-CoV-2 spike protein inhibits DNA damage repair by impeding the recruitment of DNA damage repair checkpoint proteins, a pre-requisite for V(D)J recombination in adaptive immunity. This has further been confirmed in spike protein over expressed cells by upregulation of DNA damage marker γ-H2AX .
Key clusters of genes impacted were uniquely altered by SARS-CoV-2 infection and were distinct from pH1N1. These focus on DNA damage and repair pathways and the consequent cell cycle arrest pathways. Notably we observed upregulation of LIG4, an ATP-dependent DNA ligase which acts to repair DNA double-strand breaks via the non-homologous enjoining pathway .
LIG4 expression is known to be enhanced following DNA damage and by Wnt/β-catenin signalling , suggesting that COVID-19-induced DNA damage might be responsible for induction of LIG4 in cardiac tissue. While this remains to be determined, the helicase NSP13 protein expressed by the related SARS-CoV-1 is known to induce DNA damage and replication fork stress by interacting directly with DNA polymerase δ .
Given the NSP13 protein shares 99.8% sequence homology between SARS-CoV and SARS-CoV-2, it is possible that infection may induce DNA damage within myocardial tissue. However, SARS-CoV-2 infection has been observed, at least in vitro, to induce telomere shortening .
This feature is attributed with senescence which aligns with the upregulation of this gene set pathway in COVID-19 myocardial tissues in our study. Interestingly, telomere stability is controlled by the DNA damage response proteins, as a telomere resembles a DNA break. Shortened telomeres result in a persistent DNA damage response, although at this point the function of these foci are unknown .
In cardiac tissues, we also observed that COVID-19 induced downregulation of gene clusters involved in in mitochondrial function and metabolic regulation. Mitochondrial dysfunction is linked with COVID-19 whereby SARS-CoV-2 viral proteins interact with host mitochondrial proteins .
For example, viral open reading frame 9c interacts with NDUFAF1 and NDUFAB1 [73, 74], genes we identified in our study that are required for cellular bioenergetics as part of Complex I. Indeed, SARS-CoV-2 manipulation of mitochondrial activity is likely to enable evasion of mitochondrial-mediated innate immunity [74, 75].
Dysfunctional mitochondria are also associated with myocarditis , and persistent inflammation causing irreversible myocardium damage [77, 78]. Damage to the myocardium is triggered by danger-associated molecular patterns (DAMPs), which are recognized by toll-like receptors (TLR) that are expressed on immune and heart parenchymal cells [78, 79].
Consistently, we observe upregulation of gene clusters associated with TLR signalling in heart tissue. Crucially, mitochondrial lipid, peptides and circulating mitochondrial DNA (mtDNA) are a source of DAMPs . For example, increased circulating mtDNA is detected following myocardial infarction  and can cause TLR-induced cardiomyocyte death .
Pertinently, antibodies against a key mitochondrial lipid, cardiolipin, have also been reported following serological testing of a critically ill COVID-19 patient exhibiting thrombocytopenia and coagulopathy . Indeed, the pathways and gene sets identified in our study point to a key role for SARS-CoV-2-induced cardiac injury.
However, further work is warranted to discern whether direct SARS-CoV-2 infection of cardiac tissue or other physiological events are responsible for the cardiac injury observed in our cohort.
Our study provides a comprehensive complex cellular blueprint across the full composition of cardiac tissues responding to SARS-CoV2 and H1N1 influenza using highly sophisticated spatio-temporal analyses. This study is limited by the number of samples for each cohort, in particular for the pH1N1 group and unequal sex distribution.
Targeted transcriptome panels were used which limited the number of genes profiled in the study. In addition, this analysis was restricted to autopsy samples which are unlikely to reflect the full spectrum of COVID-19 disease.
More comprehensive assessments of post-acute sequelae are needed to determine the short and long-term impacts of SARS-CoV-2 infection. It is known that DNA damage and impaired repair mechanisms foster genome instability and are involved in several chronic diseases. Long-term studies are needed to identify new onset heart disease from the early, and even subclinical, lesions as time post-infection transpires.
SARS–CoV–2 spike protein significantly inhibits DNA damage repair
Severe acute respiratory syndrome coronavirus 2 (SARS–CoV–2) is responsible for the ongoing coronavirus disease 2019 (COVID–19) pandemic that has resulted in more than 2.3 million deaths. SARS–CoV–2 is an enveloped single positive–sense RNA virus that consists of structural and non–structural proteins .
After infection, these viral pro‐ teins hijack and dysregulate the host cellular machinery to replicate, assemble, and spread progeny viruses . Recent clinical studies have shown that SARS–CoV–2 infection ex‐ traordinarily affects lymphocyte number and function [3–6].
Compared with mild and moderate survivors, patients with severe COVID–19 manifest a significantly lower num‐ ber of total T cells, helper T cells, and suppressor T cells [3,4]. Additionally, COVID–19 delays IgG and IgM levels after symptom onset [5,6].
Collectively, these clinical observa‐ tions suggest that SARS–CoV–2 affects the adaptive immune system. However, the mech‐ anism by which SARS–CoV–2 suppresses adaptive immunity remains unclear.
As two critical host surveillance systems, the immune and DNA repair systems are the primary systems that higher organisms rely on for defense against diverse threats and tissue homeostasis. Emerging evidence indicates that these two systems are interdepend‐ ent, especially during lymphocyte development and maturation .
As one of the major double‐strand DNA break (DSB) repair pathways, non‐homologous end joining (NHEJ) repair plays a critical role in lymphocyte–specific recombination–activating gene endonu‐ clease (RAG) –mediated V(D)J recombination, which results in a highly diverse repertoire of antibodies in B cell and T cell receptors (TCRs) in T cells .
For example, loss of func‐ tion of key DNA repair proteins such as ATM, DNA–PKcs, 53BP1, et al., leads to defects in the NHEJ repair which inhibit the production of functional B and T cells, leading to immunodeficiency [7,9–11]. In contrast, viral infection usually induces DNA damage via different mechanisms, such as inducing reactive oxygen species (ROS) production and host cell replication stress [12–14].
If DNA damage cannot be properly repaired, it will contribute to the amplification of viral infection‐induced pathology. Therefore, we aimed to investigate whether SARS–CoV–2 proteins hijack the DNA damage repair system, thereby affecting adaptive immunity in vitro.
reference link : https://www.researchgate.net/publication/355229973_SARS-CoV-2_Spike_Impairs_DNA_Damage_Repair_and_Inhibits_VDJ_Recombination_In_Vitro