Transcriptomic profiling of cardiac tissues from <scp>SARS‐CoV</scp>‐2 patients identifies <scp>DNA</scp> damage

Kulasinghe, Arutha; Liu, Ning; Tan, Chin Wee; Monkman, James; Sinclair, Jane E; Bhuva, Dharmesh D.; Godbolt, David; Pan, Liuliu; Nam, Andy; Sadeghirad, Habib; Sato, Kei; Bassi, Gianluigi Li; O’Byrne, K.J.; Hartmann, Camila; Miggiolaro, Anna Flavia Ribeiro dos Santos; Marques, Gustavo Lenci; Moura, Lídia Zytynski; Richard, Derek J.; Adams, Mark N.; Noronha, Lúcia de; Baena, Cristina Pellegrino; Suen, Jacky Y.; Arora, Rakesh C.; Belz, Gabrielle T.; Short, Kirsty R.; Davis, Melissa J.; Souza-Fonseca-Guimarães, Fernando

doi:10.1111/imm.13577

Cited by 22 publications

(16 citation statements)

References 84 publications

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“…Because of the mechanistic role of DNA damage in affecting most aging hallmarks 31 , including the onset of cellular senescence 32 , we next explored whether SARS-CoV-2 infection led to DNA double-strand break accumulation. Consistent with previous evidence 19,33 , we detected significantly heightened levels of phosphorylated histone H2AX at serine 139 (known as γH2AX) in SARS-CoV-2-infected organoid regions as compared to uninfected organoid cells (Fig. 4e, f), indicating increased DNA damage response marks upon SARS-CoV-2 infection.…”

Section: Sars-cov-2 Infection Triggers Cellular Senescence In the Bra...supporting

confidence: 92%

Senolytic therapy alleviates physiological human brain aging and COVID-19 neuropathology

Aguado

Amarilla

Fard

et al. 2023

Preprint

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Aging is the primary risk factor for most neurodegenerative diseases, and recently coronavirus disease 2019 (COVID-19) has been associated with severe neurological manifestations that can eventually impact neurodegenerative conditions in the long-term. The progressive accumulation of senescent cells in vivo strongly contributes to brain aging and neurodegenerative co-morbidities but the impact of virus-induced senescence in the aetiology of neuropathologies is unknown. Here, we show that senescent cells accumulate in physiologically aged brain organoids of human origin and that senolytic treatment reduces inflammation and cellular senescence; for which we found that combined treatment with the senolytic drugs dasatinib and quercetin rejuvenates transcriptomic human brain aging clocks. We further interrogated brain frontal cortex regions in postmortem patients who succumbed to severe COVID-19 and observed increased accumulation of senescent cells as compared to age-matched control brains from non-COVID-affected individuals. Moreover, we show that exposure of human brain organoids to SARS-CoV-2 evoked cellular senescence, and that spatial transcriptomic sequencing of virus-induced senescent cells identified a unique SARS-CoV-2 variant-specific inflammatory signature that is different from endogenous naturally-emerging senescent cells. Importantly, following SARS-CoV-2 infection of human brain organoids, treatment with senolytics blocked viral retention and prevented the emergence of senescent corticothalamic and GABAergic neurons. Furthermore, we demonstrate in human ACE2 overexpressing mice that senolytic treatment ameliorates COVID-19 brain pathology following infection with SARS-CoV-2. In vivo treatment with senolytics improved SARS-CoV-2 clinical phenotype and survival, alleviated brain senescence and reactive astrogliosis, promoted survival of dopaminergic neurons, and reduced viral and senescence-associated secretory phenotype gene expression in the brain. Collectively, our findings demonstrate SARS-CoV-2 can trigger cellular senescence in the brain, and that senolytic therapy mitigates senescence-driven brain aging and multiple neuropathological sequelae caused by neurotropic viruses, including SARS-CoV-2.

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Section: Sars-cov-2 Infection Triggers Cellular Senescence In the Bra...supporting

confidence: 92%

Senolytic therapy alleviates physiological human brain aging and COVID-19 neuropathology

Aguado

Amarilla

Fard

et al. 2023

Preprint

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“…Spatial transcriptomics was recently implemented using a limited COVID-19 immune panel on a Nanostring GeoMx platform in 2 COVID-19 (+) patient samples. 108 The profiling revealed the distinctive transcriptional responses to SARS-CoV-2 compared with H1N1 (influenza A virus subtype H1N1), most notably upregulation of DNA damage repair genes and mitochondrial function.…”

Section: Myocardiummentioning

confidence: 99%

Cell-Specific Mechanisms in the Heart of COVID-19 Patients

Tsai

Čiháková

Tucker

2023

Circulation Research

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From the onset of the pandemic, evidence of cardiac involvement in acute COVID-19 abounded. Cardiac presentations ranged from arrhythmias to ischemia, myopericarditis/myocarditis, ventricular dysfunction to acute heart failure, and even cardiogenic shock. Elevated serum cardiac troponin levels were prevalent among hospitalized patients with COVID-19; the higher the magnitude of troponin elevation, the greater the COVID-19 illness severity and in-hospital death risk. Whether these consequences were due to direct SARS-CoV-2 infection of cardiac cells or secondary to inflammatory responses steered early cardiac autopsy studies. SARS-CoV-2 was reportedly detected in endothelial cells, cardiac myocytes, and within the extracellular space. However, findings were inconsistent and different methodologies had their limitations. Initial autopsy reports suggested that SARS-CoV-2 myocarditis was common, setting off studies to find and phenotype inflammatory infiltrates in the heart. Nonetheless, subsequent studies rarely detected myocarditis. Microthrombi, cardiomyocyte necrosis, and inflammatory infiltrates without cardiomyocyte damage were much more common. In vitro and ex vivo experimental platforms have assessed the cellular tropism of SARS-CoV-2 and elucidated mechanisms of viral entry into and replication within cardiac cells. Data point to pericytes as the primary target of SARS-CoV-2 in the heart. Infection of pericytes can account for the observed pericyte and endothelial cell death, innate immune response, and immunothrombosis commonly observed in COVID-19 hearts. These processes are bidirectional and synergistic, rendering a definitive order of events elusive. Single-cell/nucleus analyses of COVID-19 myocardial tissue and isolated cardiac cells have provided granular data about the cellular composition and cell type–specific transcriptomic signatures of COVID-19 and microthrombi-positive COVID-19 hearts. Still, much remains unknown and more in vivo studies are needed. This review seeks to provide an overview of the current understanding of COVID-19 cardiac pathophysiology. Cell type–specific mechanisms and the studies that provided such insights will be highlighted. Given the unprecedented pace of COVID-19 research, more mechanistic details are sure to emerge since the writing of this review. Importantly, our current knowledge offers significant clues about the cardiac pathophysiology of long COVID-19, the increased postrecovery risk of cardiac events, and thus, the future landscape of cardiovascular disease.

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“…Evidence for a DNA-damaging effect of SARS-CoV-2 - and perhaps CoV-2 S - is accumulating ( 23 , 36 , 280 – 283 ). Comet assays and γ-H2AX immunostaining revealed elevated levels of DNA damage in SARS-CoV-2-infected Huh7 or Vero-6 (African green monkey kidney) cells ( 66 , 190 , 284 , 285 ), but also in lymphocytes and cardiac tissue of deceased COVID-19 patients ( 286 – 288 ). In the human studies, DNA damage levels correlated with Il-6 expression in infected cells ( 285 ) and serum levels of IL-6 ( 287 ) and of other inflammatory ILs ( 286 ).…”

Section: Spike and Dsdna Sensors In The Adverse Events After Covid-19...mentioning

confidence: 99%

“…In the human studies, DNA damage levels correlated with Il-6 expression in infected cells ( 285 ) and serum levels of IL-6 ( 287 ) and of other inflammatory ILs ( 286 ). Post-mortem transcriptomic analyses of cardiac tissues of COVID-19 patients revealed an enrichment of DNA damage and repair, heat shock, and cell cycle control among the predominant upregulated genes ( 288 ). An increase in oxidative stress and in the number of DSBs has been observed in PBMCs from older individuals at 24 h after vaccination with BNT162B2 ( 280 ), and several p53-controlled genes, including those related to apoptosis and DNA-repair, were overexpressed in PBMCs from a patient who developed myocarditis after BNT162b2 vaccination (hence, likely as a consequence of CoV-2 S expression in the absence of infection) ( 289 ).…”

Section: Spike and Dsdna Sensors In The Adverse Events After Covid-19...mentioning

confidence: 99%

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

Heil

2024

Front. Immunol.

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The coronavirus disease 2019 (COVID-19) pandemic triggered an unprecedented concentration of economic and research efforts to generate knowledge at unequalled speed on deregulated interferon type I signalling and nuclear factor kappa light chain enhancer in B-cells (NF-κB)-driven interleukin (IL)-1β, IL-6, IL-18 secretion causing cytokine storms. The translation of the knowledge on how the resulting systemic inflammation can lead to life-threatening complications into novel treatments and vaccine technologies is underway. Nevertheless, previously existing knowledge on the role of cytoplasmatic or circulating self-DNA as a pro-inflammatory damage-associated molecular pattern (DAMP) was largely ignored. Pathologies reported ‘de novo’ for patients infected with Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV)-2 to be outcomes of self-DNA-driven inflammation in fact had been linked earlier to self-DNA in different contexts, e.g., the infection with Human Immunodeficiency Virus (HIV)-1, sterile inflammation, and autoimmune diseases. I highlight particularly how synergies with other DAMPs can render immunogenic properties to normally non-immunogenic extracellular self-DNA, and I discuss the shared features of the gp41 unit of the HIV-1 envelope protein and the SARS-CoV 2 Spike protein that enable HIV-1 and SARS-CoV-2 to interact with cell or nuclear membranes, trigger syncytia formation, inflict damage to their host’s DNA, and trigger inflammation – likely for their own benefit. These similarities motivate speculations that similar mechanisms to those driven by gp41 can explain how inflammatory self-DNA contributes to some of most frequent adverse events after vaccination with the BNT162b2 mRNA (Pfizer/BioNTech) or the mRNA-1273 (Moderna) vaccine, i.e., myocarditis, herpes zoster, rheumatoid arthritis, autoimmune nephritis or hepatitis, new-onset systemic lupus erythematosus, and flare-ups of psoriasis or lupus. The hope is to motivate a wider application of the lessons learned from the experiences with COVID-19 and the new mRNA vaccines to combat future non-COVID-19 diseases.

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Transcriptomic profiling of cardiac tissues from SARS‐CoV‐2 patients identifies DNA damage

Cited by 22 publications

References 84 publications

Senolytic therapy alleviates physiological human brain aging and COVID-19 neuropathology

Senolytic therapy alleviates physiological human brain aging and COVID-19 neuropathology

Cell-Specific Mechanisms in the Heart of COVID-19 Patients

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

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