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1.
J Reprod Immunol ; 151: 103635, 2022 06.
Article in English | MEDLINE | ID: covidwho-1885957

ABSTRACT

The reproductive system can be infected by a variety of double-stranded RNA viruses, which disrupt ovary function and pregnancy. However, whether viral infection directly affects early embryonic development remains unknown. Here we show that Poly(I:C), which mimics a double-stranded RNA virus, significantly impaired mouse early embryonic development in vitro, and up-regulated TLR3 and IFNα at the two cells embryo stage. Further studies indicated that Poly(I:C)-treatment caused DNA damage and abnormal spindle morphology at the first cleavage. Moreover, CDX2 and SOX2 expression was decreased while blastocyst cell apoptosis was increased. Altogether, Poly(I:C) decreased the rate of successful in vitro fertilization via DNA damage and abnormal spindle morphology at the first cleavage and inhibited early embryonic development by inducing immune response and promoting blastocyst cell apoptosis. This study provides an implication for exploring the causes of reproductive disorders in mammals and humans caused by infection of double-stranded RNA virus.


Subject(s)
Embryonic Development , RNA, Double-Stranded , Animals , Blastocyst , DNA Damage , Female , Fertilization in Vitro , Humans , Mammals/genetics , Mice , Pregnancy
2.
Immun Inflamm Dis ; 10(7): e638, 2022 Jul.
Article in English | MEDLINE | ID: covidwho-1885399

ABSTRACT

BACKGROUND: The outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-COV-2) in 2020 has led to millions of deaths worldwide. Case reports suggested that infection of SARS-CoV-2 is potentially associated with occurrences of cardiovascular pathology. However, the mode of action and mechanisms of SARS-CoV-2 influencing cardiomyocytes still remain largely unclear. AIMS: To explore the mechanisms underlying cardiomyocytes damage induced by SARS-CoV-2 infection. MATERIALS & METHODS: the serum markers of cardiovascular injury were analyzed by ELISA. The isolated SARS-CoV-2 virus were co-cultured with human cardiomyocytes (AC16) and immunofluorescence assay was used evaluate the invasion of virus. Moreover, serum obtained from acute stage of SARS-CoV-2 infected patients and healthy controls were used to incubate with AC16 cells, then indicators associated with cell stress and DNA damage were analyzed by Western-blot. RESULTS: we found that high-sensitivity troponin T (hsTnT), an indicator of cardiovascular disease, was higher in the acute stage of COVID-19. Additionally, in vitro coculture of SARS-CoV-2 and AC16 cells showed almost no infectious ability of SARS-CoV-2 to directly infect AC16 cells. Results of serum treatment suggested that serum from infected subjects induced cell stress (upregulation of p53 and HSP70) and elevation of DNA damage risk (increased γH2Ax and H3K79me2) in AC16. DISCUSSION: our observations indicated a hard way for SARS-CoV-2 to infect cardiomyocytes directly. However, infection-induced immune storm in serum could bring stress and elevated DNA damage risks to cardiovascular system. CONCLUSION: These findings indicated the possibilities of SARS-CoV-2 inducing stress and elevating DNA damage risk to cardiomyocytes without direct infection.


Subject(s)
COVID-19 , SARS-CoV-2 , DNA Damage , Humans , Myocytes, Cardiac/pathology
3.
Biochim Biophys Acta Mol Basis Dis ; 1868(6): 166393, 2022 06 01.
Article in English | MEDLINE | ID: covidwho-1748209

ABSTRACT

Immune senescence in the elderly has been associated with chronic oxidative stress and DNA damage accumulation. Herein we tested the hypothesis that increased endogenous DNA damage and oxidative stress in peripheral blood mononuclear cells of older adults associate with diminished humoral immune response to SARS-CoV-2 vaccination. Increased oxidative stress and DNA double-strand breaks (DSBs) were detected in 9 non-immunocompromised individuals aged 80-96 years compared to 11 adults aged 27-44 years, before, as well as on days 1 and 14 after the first dose, and on day 14 after the second dose of the BNT162B2-mRNA vaccine (all p < 0.05). SARS-CoV-2 vaccination induced a resolvable increase in oxidative stress and DNA damage, but individual DSB-repair efficiency was unaffected by vaccination irrespective of age, confirming vaccination safety. Individual titers of anti-Spike-Receptor Binding Domain (S-RBD)-IgG antibodies, and the neutralizing capacity of circulating anti-SARS-CoV-2 antibodies, measured on day 14 after the second dose in all participants, correlated inversely with the corresponding pre-vaccination endogenous oxidative stress and DSB levels (all p < 0.05). In particular, a strong inverse correlation of individual pre-vaccination DSB levels with both the respective anti-S-RBD-IgG antibodies titers (r = -0.867) and neutralizing capacity of circulating anti-SARS-CoV-2 antibodies (r = -0.983) among the 9 older adults was evident. These findings suggest that humoral responses to SARS-CoV-2 vaccination may be weaker when immune cells are under oxidative and/or genomic stress. Whether such measurements may serve as biomarkers of vaccine efficacy in older adults warrants further studies.


Subject(s)
COVID-19 , Adult , Aged , Aged, 80 and over , COVID-19/prevention & control , COVID-19 Vaccines/adverse effects , DNA Damage , Humans , Leukocytes, Mononuclear , Oxidative Stress , SARS-CoV-2 , Vaccination , Vaccines, Synthetic
4.
Sci Total Environ ; 825: 153988, 2022 Jun 15.
Article in English | MEDLINE | ID: covidwho-1692891

ABSTRACT

The identification of SARS-CoV-2 particles in wastewater and freshwater ecosystems has raised concerns about its possible impacts on non-target aquatic organisms. In this particular, our knowledge of such impacts is still limited, and little attention has been given to this issue. Hence, in our study, we aimed to evaluate the possible induction of mutagenic (via micronucleus test) and genotoxic (via single cell gel electrophoresis assay, comet assay) effects in Poecilia reticulata adults exposed to fragments of the Spike protein of the new coronavirus at the level of 40 µg/L, denominated PSPD-2002. As a result, after 10 days of exposure, we have found that animals exposed to the peptides demonstrated an increase in the frequency of erythrocytic nuclear alteration (ENA) and all parameters assessed in the comet assay (length tail, %DNA in tail and Olive tail moment), suggesting that PSPD-2002 peptides were able to cause genomic instability and erythrocyte DNA damage. Besides, these effects were significantly correlated with the increase in lipid peroxidation processes [inferred by the high levels of malondialdehyde (MDA)] reported in the brain and liver of P. reticulata and with the reduction of the superoxide dismutase (SOD) and catalase (CAT) activity. Thus, our study constitutes a new insight and promising investigation into the toxicity associated with the dispersal of SARS-CoV-2 peptide fragments in freshwater environments.


Subject(s)
COVID-19 , Poecilia , Water Pollutants, Chemical , Animals , Comet Assay , DNA Damage , Ecosystem , Genomic Instability , Humans , Pandemics , Peptides , SARS-CoV-2 , Water Pollutants, Chemical/analysis , Water Pollutants, Chemical/toxicity
5.
Mutat Res Rev Mutat Res ; 789: 108411, 2022.
Article in English | MEDLINE | ID: covidwho-1636268

ABSTRACT

The coronavirus disease-2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is challenging global health and economic systems. In some individuals, COVID-19 can cause a wide array of symptoms, affecting several organs, such as the lungs, heart, bowels, kidneys and brain, causing multiorgan failure, sepsis and death. These effects are related in part to direct viral infection of these organs, immunological deregulation, a hypercoagulatory state and the potential for development of cytokine storm syndrome. Since the appearance of COVID-19 is recent, the long-term effects on the health of recovered patients remain unknown. In this review, we focused on current evidence of the mechanisms of DNA damage mediated by coronaviruses. Data supports that these viruses can induce DNA damage, genomic instability, and cell cycle deregulation during their replication in mammalian cells. Since the induction of DNA damage and aberrant DNA repair mechanisms are related to the development of chronic diseases such as cancer, diabetes, neurodegenerative disorders, and atherosclerosis, it will be important to address similar effects and outcomes in recovered COVID-19 patients.


Subject(s)
COVID-19 , Animals , DNA Damage/genetics , Humans , Lung , Mammals , SARS-CoV-2
6.
Environ Sci Pollut Res Int ; 29(23): 33988-33998, 2022 May.
Article in English | MEDLINE | ID: covidwho-1626110

ABSTRACT

Organisms are increasingly exposed to ultraviolet (UV) rays of sunlight, due to the thinning of the ozone layer and its widespread use in sterilization processes, especially against the SARS-CoV-2 virus. The present study was conducted with the purpose of evaluating the damages of UV-A and UV-C radiations in Allium cepa L. roots. The effects of two different types of UV on some physiological, biochemical, cytogenotoxic, and anatomical parameters were investigated in a multifaceted study. Three groups were formed from Allium bulbs, one of which was the control group. One of the other groups was exposed to 254 nm (UV-C) and the other to 365 nm (UV-A) UV. Growth retardation effect of UV was investigated with respect to germination percentage, total weight gain, and root elongation, while cytogenotoxicity arisen from UV exposure was analyzed using mitotic index (MI) and chromosomal aberration (CA) and micronucleus (MN) frequency. Oxidative stress due to UV application was investigated based on the accumulation of malondialdehyde (MDA) and the total activities of superoxide dismutase (SOD) and catalase (CAT) enzymes. Also, anatomical changes induced by UV-A and UV-C were analyzed in root meristematic cells. UV treatments caused significant reductions in growth-related parameters. Both UV treatments caused a significant increase in MDA levels and induction of SOD and CAT enzymes in root meristematic cells. A decrease in MI and an increase in the frequency of MN and CAs were observed in root tip cells, indicating the cytogenotoxic effect of UV application. Anatomical damages such as epidermis cell damage, cortex cell damage, necrotic zones, giant cell nucleus, and indistinct transmission tissue occurred in cells exposed to UV. All of the physiological, biochemical, cytogenetic, and anatomical damages observed in this study were more severe in cells treated with UV-C compared to UV-A. This study suggested that UV exposure triggered growth inhibition, cytogenotoxicity, oxidative stress, and meristematic cell damages in A. cepa roots depending on the wavelength.


Subject(s)
Allium , COVID-19 , DNA Damage , Onions , Plant Roots , SARS-CoV-2 , Superoxide Dismutase
7.
Environ Mol Mutagen ; 63(1): 37-63, 2022 01.
Article in English | MEDLINE | ID: covidwho-1620131

ABSTRACT

This review considers antiviral nucleoside analog drugs, including ribavirin, favipiravir, and molnupiravir, which induce genome error catastrophe in SARS-CoV or SARS-CoV-2 via lethal mutagenesis as a mode of action. In vitro data indicate that molnupiravir may be 100 times more potent as an antiviral agent than ribavirin or favipiravir. Molnupiravir has recently demonstrated efficacy in a phase 3 clinical trial. Because of its anticipated global use, its relative potency, and the reported in vitro "host" cell mutagenicity of its active principle, ß-d-N4-hydroxycytidine, we have reviewed the development of molnupiravir and its genotoxicity safety evaluation, as well as the genotoxicity profiles of three congeners, that is, ribavirin, favipiravir, and 5-(2-chloroethyl)-2'-deoxyuridine. We consider the potential genetic risks of molnupiravir on the basis of all available information and focus on the need for additional human genotoxicity data and follow-up in patients treated with molnupiravir and similar drugs. Such human data are especially relevant for antiviral NAs that have the potential of permanently modifying the genomes of treated patients and/or causing human teratogenicity or embryotoxicity. We conclude that the results of preclinical genotoxicity studies and phase 1 human clinical safety, tolerability, and pharmacokinetics are critical components of drug safety assessments and sentinels of unanticipated adverse health effects. We provide our rationale for performing more thorough genotoxicity testing prior to and within phase 1 clinical trials, including human PIG-A and error corrected next generation sequencing (duplex sequencing) studies in DNA and mitochondrial DNA of patients treated with antiviral NAs that induce genome error catastrophe via lethal mutagenesis.


Subject(s)
Antiviral Agents/adverse effects , COVID-19/drug therapy , Cytidine/analogs & derivatives , DNA Damage/drug effects , Hydroxylamines/adverse effects , Nucleosides/adverse effects , SARS-CoV-2/genetics , Amides/adverse effects , Amides/therapeutic use , Antiviral Agents/therapeutic use , Cytidine/adverse effects , Cytidine/therapeutic use , Deoxyuridine/adverse effects , Deoxyuridine/analogs & derivatives , Deoxyuridine/therapeutic use , Genome, Human/drug effects , Humans , Hydroxylamines/therapeutic use , Mutagenesis/drug effects , Nucleosides/therapeutic use , Pyrazines/adverse effects , Pyrazines/therapeutic use , Ribavirin/adverse effects , Ribavirin/therapeutic use , SARS-CoV-2/drug effects
8.
Fertil Steril ; 117(2): 287-296, 2022 02.
Article in English | MEDLINE | ID: covidwho-1587766

ABSTRACT

OBJECTIVE: To study the contagiousness of sperm and its influence on fertility after recovery from COVID-19 infection. DESIGN: Prospective cohort study. SETTING: University medical center. PATIENT(S): One hundred twenty Belgian men who had recovered from proven COVID-19 infection. INTERVENTION(S): No intervention was performed. MAIN OUTCOME MEASURE(S): Semen quality was assessed using the World Health Organisation criteria. DNA damage to sperm cells was assessed by quantifying the DNA fragmentation index and the high density stainability. Finally antibodies against SARS-CoV2 spike-1 antigen, nuclear and S1-receptor binding domain were measured by Elisa and chemilumenscent microparticle immunoassays, respectively. RESULT(S): SARS-CoV-2 RNA was not detected in semen during the period shortly after infection nor at a later time. Mean progressive motility was reduced in 60% of men tested shortly (<1 month) after COVID-19 infection, 37% of men tested 1 to 2 months after COVID-19 infection, and 28% of men tested >2 months after COVID-19 infection. Mean sperm count was reduced in 37% of men tested shortly (<1 month) after COVID-19 infection, 29% of men tested 1 to 2 months after COVID-19 infection, and 6% of men tested >2 months after COVID-19 infection. The severity of COVID-19 infection and the presence of fever were not correlated with sperm characteristics, but there were strong correlations between sperm abnormalities and the titers of SARS-CoV-2 IgG antibody against spike 1 and the receptor- binding domain of spike 1, but not against nucleotide, in serum. High levels of antisperm antibodies developed in three men (2.5%). CONCLUSION(S): Semen is not infectious with SARS-CoV-2 at 1 week or more after COVID-19 infection (mean, 53 days). However, couples with a desire for pregnancy should be warned that sperm quality after COVID-19 infection can be suboptimal. The estimated recovery time is 3 months, but further follow-up studies are under way to confirm this and to determine if permanent damage occurred in a minority of men.


Subject(s)
COVID-19 Nucleic Acid Testing/methods , COVID-19/virology , RNA, Viral/analysis , SARS-CoV-2/genetics , Semen/virology , Spermatozoa/physiology , Adult , Antibodies, Viral/analysis , Antibodies, Viral/blood , COVID-19/transmission , DNA Damage , DNA Fragmentation , Humans , Immunoglobulin G/blood , Infertility, Male/virology , Male , Prospective Studies , SARS-CoV-2/immunology , Semen Analysis , Sperm Count , Sperm Motility , Spermatozoa/abnormalities , Spermatozoa/chemistry , Spike Glycoprotein, Coronavirus/immunology
9.
EMBO Rep ; 23(2): e53658, 2022 02 03.
Article in English | MEDLINE | ID: covidwho-1547826

ABSTRACT

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes the coronavirus disease 2019 (COVID-19), known to be more common in the elderly, who also show more severe symptoms and are at higher risk of hospitalization and death. Here, we show that the expression of the angiotensin converting enzyme 2 (ACE2), the SARS-CoV-2 cell receptor, increases during aging in mouse and human lungs. ACE2 expression increases upon telomere shortening or dysfunction in both cultured mammalian cells and in vivo in mice. This increase is controlled at the transcriptional level, and Ace2 promoter activity is DNA damage response (DDR)-dependent. Both pharmacological global DDR inhibition of ATM kinase activity and selective telomeric DDR inhibition by the use of antisense oligonucleotides prevent Ace2 upregulation following telomere damage in cultured cells and in mice. We propose that during aging telomere dysfunction due to telomeric shortening or damage triggers DDR activation and this causes the upregulation of ACE2, the SARS-CoV-2 cell receptor, thus contributing to make the elderly more susceptible to the infection.


Subject(s)
Aging , Angiotensin-Converting Enzyme 2/genetics , COVID-19 , DNA Damage , Telomere , Aged , Aging/genetics , Animals , Humans , Mice , SARS-CoV-2 , Telomere/genetics
10.
Molecules ; 26(22)2021 Nov 22.
Article in English | MEDLINE | ID: covidwho-1534202

ABSTRACT

The 5',8-cyclo-2'-deoxypurines (cdPus) affect the DNA structure. When these bulky structures are a part of clustered DNA lesions (CDL), they affect the repair of the other lesions within the cluster. Mitochondria are crucial for cell survival and have their own genome, hence, are highly interesting in the context of CDL repair. However, no studies are exploring this topic. Here, the initial stages of mitochondrial base excision repair (mtBER) were considered-the strand incision and elongation. The repair of a single lesion (apurinic site (AP site)) accompanying the cdPu within the double-stranded CDL has been investigated for the first time. The type of cdPu, its diastereomeric form, and the interlesion distance were taken into consideration. For these studies, the established experimental model of short oligonucleotides (containing AP sites located ≤7 base pairs to the cdPu in both directions) and mitochondrial extracts of the xrs5 cells were used. The obtained results have shown that the presence of cdPus influenced the processing of an AP site within the CDL. Levels of strand incision and elongation were higher for oligos containing RcdA and ScdG than for those with ScdA and RcdG. Investigated stages of mtBER were more efficient for DNA containing AP sites located on 5'-end side of cdPu than on its 3'-end side. In conclusion, the presence of cdPus in mtDNA structure may affect mtBER (processing the second mutagenic lesion within the CDL). As impaired repair processes may lead to serious biological consequences, further studies concerning the mitochondrial repair of CDL are highly demanded.


Subject(s)
DNA Damage , DNA Repair , DNA, Mitochondrial/metabolism , Oligonucleotides , Purine Nucleosides , Animals , CHO Cells , Cricetulus , Oligonucleotides/chemistry , Oligonucleotides/pharmacology , Purine Nucleosides/chemistry , Purine Nucleosides/pharmacology
12.
Sci Rep ; 11(1): 21075, 2021 10 26.
Article in English | MEDLINE | ID: covidwho-1493212

ABSTRACT

Bats are potential natural reservoirs for emerging viruses, causing deadly human diseases, such as COVID-19, MERS, SARS, Nipah, Hendra, and Ebola infections. The fundamental mechanisms by which bats are considered "living bioreactors" for emerging viruses are not fully understood. Some studies suggest that tolerance to viruses is linked to suppressing antiviral immune and inflammatory responses due to DNA damage by energy generated to fly. Our study reveals that bats' gut bacteria could also be involved in the host and its microbiota's DNA damage. We performed screening of lactic acid bacteria and bacilli isolated from bats' feces for mutagenic and oxidative activity by lux-biosensors. The pro-mutagenic activity was determined when expression of recA increased with the appearance of double-strand breaks in the cell DNA, while an increase of katG expression in the presence of hydroxyl radicals indicated antioxidant activity. We identified that most of the isolated bacteria have pro-mutagenic and antioxidant properties at the same time. This study reveals new insights into bat gut microbiota's potential involvement in antiviral response and opens new frontiers in preventing emerging diseases originating from bats.


Subject(s)
Chiroptera/virology , Gastrointestinal Microbiome , Mutagens , Animals , Antioxidants/metabolism , Antiviral Agents , Bacillus , Bacterial Proteins/genetics , Biosensing Techniques , COVID-19 , DNA , DNA Damage , Disease Reservoirs/virology , Escherichia coli/metabolism , Feces , Immune System , Inflammation , Lactic Acid/metabolism , Mass Spectrometry , Mutagenesis , Oxidative Stress , Rec A Recombinases/metabolism , SARS-CoV-2 , Viruses/isolation & purification , Zoonoses/virology
13.
In Vivo ; 35(6): 3495-3499, 2021.
Article in English | MEDLINE | ID: covidwho-1485631

ABSTRACT

BACKGROUND/AIM: COVID-19 may lead to progressive respiratory failure as a consequence of alveolar damage, resulting in death. The aim of this study was to evaluate cytogenetic damage in oral cells of COVID-19 patients by micronucleus assay. PATIENTS AND METHODS: A total of 11 COVID-19 patients aged 40.7±9.3 years (5 men and 6 women) were included in this study. For the control group, a total of 15 participants not infected with SARS-CoV-2 virus were included. The mean age was 41.6±6.2 years (5 men and 10 women). RESULTS: The results showed statistically significant differences (p<0.05) in micronucleated buccal mucosa cells of COVID-19 patients. In addittion, a statistically significant increase in karyolysis and karrhyorexis (p<0.05) was observed in COVID-19 patients compared to control. CONCLUSION: SARS-CoV-2 virus can induce mutagenesis and cytotoxicity in oral cells.


Subject(s)
COVID-19 , Mouth Mucosa , Adult , Biological Monitoring , Cytogenetic Analysis , DNA Damage , Female , Humans , Male , Micronucleus Tests , Middle Aged , SARS-CoV-2
14.
Biol Direct ; 16(1): 20, 2021 10 21.
Article in English | MEDLINE | ID: covidwho-1477450

ABSTRACT

SARS-CoV-2 infection could cause severe acute respiratory syndrome, largely attributed to dysregulated immune activation and extensive lung tissue damage. However, the underlying mechanisms are not fully understood. Here, we reported that viral infection could induce syncytia formation within cells expressing ACE2 and the SARS-CoV-2 spike protein, leading to the production of micronuclei with an average rate of about 4 per syncytium (> 93%). Remarkably, these micronuclei were manifested with a high level of activation of both DNA damage response and cGAS-STING signaling, as indicated by micronucleus translocation of γH2Ax and cGAS, and upregulation of their respective downstream target genes. Since activation of these signaling pathways were known to be associated with cellular catastrophe and aberrant immune activation, these findings help explain the pathological effects of SARS-CoV-2 infection at cellular and molecular levels, and provide novel potential targets for COVID-19 therapy.


Subject(s)
COVID-19/genetics , COVID-19/metabolism , DNA Damage , Membrane Proteins/metabolism , Nucleotidyltransferases/metabolism , SARS-CoV-2/pathogenicity , Angiotensin-Converting Enzyme 2/genetics , Angiotensin-Converting Enzyme 2/metabolism , COVID-19/virology , Giant Cells/metabolism , Giant Cells/virology , HeLa Cells , Humans , Micronucleus Tests , SARS-CoV-2/genetics , SARS-CoV-2/metabolism , Signal Transduction , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/metabolism
15.
Viruses ; 13(10)2021 10 13.
Article in English | MEDLINE | ID: covidwho-1470992

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has led to the coronavirus disease 2019 (COVID-19) pandemic, severely affecting public health and the global economy. Adaptive immunity plays a crucial role in fighting against SARS-CoV-2 infection and directly influences the clinical outcomes of patients. Clinical studies have indicated that patients with severe COVID-19 exhibit delayed and weak adaptive immune responses; however, the mechanism by which SARS-CoV-2 impedes adaptive immunity remains unclear. Here, by using an in vitro cell line, we report that the SARS-CoV-2 spike protein significantly inhibits DNA damage repair, which is required for effective V(D)J recombination in adaptive immunity. Mechanistically, we found that the spike protein localizes in the nucleus and inhibits DNA damage repair by impeding key DNA repair protein BRCA1 and 53BP1 recruitment to the damage site. Our findings reveal a potential molecular mechanism by which the spike protein might impede adaptive immunity and underscore the potential side effects of full-length spike-based vaccines.


Subject(s)
Adaptive Immunity/immunology , COVID-19/pathology , DNA Repair/genetics , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/genetics , V(D)J Recombination/genetics , Antibodies, Neutralizing/blood , Antibodies, Neutralizing/immunology , Antibodies, Viral/blood , Antibodies, Viral/immunology , BRCA1 Protein/antagonists & inhibitors , CD4 Lymphocyte Count , CD8-Positive T-Lymphocytes/immunology , COVID-19 Vaccines/immunology , Cell Line , DNA Damage/genetics , HEK293 Cells , Humans , Immunity, Humoral/immunology , SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus/immunology , T-Lymphocytes, Helper-Inducer/immunology , Tumor Suppressor p53-Binding Protein 1/antagonists & inhibitors
16.
Biochem Biophys Res Commun ; 579: 141-145, 2021 11 19.
Article in English | MEDLINE | ID: covidwho-1446456

ABSTRACT

The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus responsible for the current COVID-19 pandemic and has now infected more than 200 million people with more than 4 million deaths globally. Recent data suggest that symptoms and general malaise may continue long after the infection has ended in recovered patients, suggesting that SARS-CoV-2 infection has profound consequences in the host cells. Here we report that SARS-CoV-2 infection can trigger a DNA damage response (DDR) in African green monkey kidney cells (Vero E6). We observed a transcriptional upregulation of the Ataxia telangiectasia and Rad3 related protein (ATR) in infected cells. In addition, we observed enhanced phosphorylation of CHK1, a downstream effector of the ATR DNA damage response, as well as H2AX. Strikingly, SARS-CoV-2 infection lowered the expression of TRF2 shelterin-protein complex, and reduced telomere lengths in infected Vero E6 cells. Thus, our observations suggest SARS-CoV-2 may have pathological consequences to host cells beyond evoking an immunopathogenic immune response.


Subject(s)
COVID-19/genetics , DNA Damage , Host-Pathogen Interactions/genetics , SARS-CoV-2/pathogenicity , Animals , Ataxia Telangiectasia Mutated Proteins/genetics , Checkpoint Kinase 1/metabolism , Chlorocebus aethiops , Histones/genetics , Phosphorylation , Telomere , Vero Cells
17.
Nat Commun ; 12(1): 4918, 2021 08 13.
Article in English | MEDLINE | ID: covidwho-1397870

ABSTRACT

Ribosomal RNA genes (rDNA) are highly unstable and susceptible to rearrangement due to their repetitive nature and active transcriptional status. Sequestration of rDNA in the nucleolus suppresses uncontrolled recombination. However, broken repeats must be first released to the nucleoplasm to allow repair by homologous recombination. Nucleolar release of broken rDNA repeats is conserved from yeast to humans, but the underlying molecular mechanisms are currently unknown. Here we show that DNA damage induces phosphorylation of the CLIP-cohibin complex, releasing membrane-tethered rDNA from the nucleolus in Saccharomyces cerevisiae. Downstream of phosphorylation, SUMOylation of CLIP-cohibin is recognized by Ufd1 via its SUMO-interacting motif, which targets the complex for disassembly through the Cdc48/p97 chaperone. Consistent with a conserved mechanism, UFD1L depletion in human cells impairs rDNA release. The dynamic and regulated assembly and disassembly of the rDNA-tethering complex is therefore a key determinant of nucleolar rDNA release and genome integrity.


Subject(s)
Cell Nucleolus/genetics , DNA Repair , DNA, Ribosomal/genetics , Saccharomyces cerevisiae Proteins/genetics , Small Ubiquitin-Related Modifier Proteins/genetics , Valosin Containing Protein/genetics , Cell Cycle Proteins/genetics , Cell Cycle Proteins/metabolism , Cell Nucleolus/metabolism , DNA Damage , DNA, Ribosomal/metabolism , Humans , Membrane Proteins/genetics , Membrane Proteins/metabolism , Mutation , Nuclear Proteins/genetics , Nuclear Proteins/metabolism , Phosphorylation , Protein Binding , Saccharomyces cerevisiae/genetics , Saccharomyces cerevisiae/metabolism , Saccharomyces cerevisiae Proteins/metabolism , Small Ubiquitin-Related Modifier Proteins/metabolism , Sumoylation , Two-Hybrid System Techniques , Valosin Containing Protein/metabolism
18.
Chemosphere ; 286(Pt 3): 131898, 2022 Jan.
Article in English | MEDLINE | ID: covidwho-1356165

ABSTRACT

Microplastics (MPs) are ubiquitous anthropogenic contaminants, and their abundance in the entire ecosystem raises the question of how far is the impact of these MPs on the biota, humans, and the environment. Recent research has overemphasized the occurrence, characterization, and direct toxicity of MPs; however, determining and understanding their genotoxic effect is still limited. Thus, the present review addresses the genotoxic potential of these emerging contaminants in aquatic organisms and in human peripheral lymphocytes and identified the research gaps in this area. Several genotoxic endpoints were implicated, including the frequency of micronuclei (MN), nucleoplasmic bridge (NPB), nuclear buds (NBUD), DNA strand breaks, and the percentage of DNA in the tail (%Tail DNA). In addition, the mechanism of MPs-induced genotoxicity seems to be closely associated with reactive oxygen species (ROS) production, inflammatory responses, and DNA repair interference. However, the gathered information urges the need for more studies that present environmentally relevant conditions. Taken into consideration, the lifestyle changes within the COVID-19 pandemic, we discussed the impact of the pandemic on enhancing the genotoxic potential of MPs whether through increasing human exposure to MPs via inappropriate disposal and overconsumption of plastic-based products or by disrupting the defense system owing to unhealthy food and sleep deprivation as well as stress. Overall, this review provided a reference for the genotoxic effect of MPs, their mechanism of action, as well as the contribution of COVID-19 to increase the genotoxic risk of MPs.


Subject(s)
COVID-19 , Water Pollutants, Chemical , DNA Damage , Ecosystem , Humans , Microplastics , Pandemics , Plastics/toxicity , SARS-CoV-2 , Water Pollutants, Chemical/analysis , Water Pollutants, Chemical/toxicity
19.
Clin Immunol ; 229: 108765, 2021 08.
Article in English | MEDLINE | ID: covidwho-1252592

ABSTRACT

Whether and how an acute immune challenge may affect DNA Damage Response (DDR) is unknown. By studying vaccinations against Influenza and SARS-CoV-2 (mRNA-based) we found acute increases of type-I interferon-inducible gene expression, oxidative stress and DNA damage accumulation in blood mononuclear cells of 9 healthy controls, coupled with effective anti-SARS-CoV-2 neutralizing antibody production in all. Increased DNA damage after SARS-CoV-2 vaccine, partly due to increased oxidative stress, was transient, whereas the inherent DNA repair capacity was found intact. In contrast, in 26 patients with Systemic Lupus Erythematosus, who served as controls in the context of chronic immune activation, we validated increased DNA damage accumulation, increased type-I interferon-inducible gene expression and induction of oxidative stress, however aberrant DDR was associated with deficiencies in nucleotide excision repair pathways. These results indicate that acute immune challenge can indeed activate DDR pathways, whereas, contrary to chronic immune challenge, successful repair of DNA lesions occurs.


Subject(s)
Antibodies, Neutralizing/physiology , COVID-19 Vaccines/immunology , COVID-19/prevention & control , DNA Damage , Lupus Erythematosus, Systemic/immunology , SARS-CoV-2/immunology , Adolescent , Adult , Aged , COVID-19/pathology , Case-Control Studies , Female , Gene Expression Regulation/immunology , Humans , Interferon Type I/metabolism , Male , Middle Aged , Oxidative Stress , Vaccines, Synthetic/immunology , Young Adult
20.
PLoS Pathog ; 17(6): e1009596, 2021 06.
Article in English | MEDLINE | ID: covidwho-1249581

ABSTRACT

The rapid evolution of RNA viruses has been long considered to result from a combination of high copying error frequencies during RNA replication, short generation times and the consequent extensive fixation of neutral or adaptive changes over short periods. While both the identities and sites of mutations are typically modelled as being random, recent investigations of sequence diversity of SARS coronavirus 2 (SARS-CoV-2) have identified a preponderance of C->U transitions, proposed to be driven by an APOBEC-like RNA editing process. The current study investigated whether this phenomenon could be observed in datasets of other RNA viruses. Using a 5% divergence filter to infer directionality, 18 from 36 datasets of aligned coding region sequences from a diverse range of mammalian RNA viruses (including Picornaviridae, Flaviviridae, Matonaviridae, Caliciviridae and Coronaviridae) showed a >2-fold base composition normalised excess of C->U transitions compared to U->C (range 2.1x-7.5x), with a consistently observed favoured 5' U upstream context. The presence of genome scale RNA secondary structure (GORS) was the only other genomic or structural parameter significantly associated with C->U/U->C transition asymmetries by multivariable analysis (ANOVA), potentially reflecting RNA structure dependence of sites targeted for C->U mutations. Using the association index metric, C->U changes were specifically over-represented at phylogenetically uninformative sites, potentially paralleling extensive homoplasy of this transition reported in SARS-CoV-2. Although mechanisms remain to be functionally characterised, excess C->U substitutions accounted for 11-14% of standing sequence variability of structured viruses and may therefore represent a potent driver of their sequence diversification and longer-term evolution.


Subject(s)
Mammals/virology , Mutation , RNA Viruses/genetics , SARS-CoV-2/genetics , APOBEC Deaminases/metabolism , Animals , Base Sequence , COVID-19/virology , Cytidine/genetics , DNA Damage/physiology , Evolution, Molecular , Gene Expression Regulation, Viral , Genome, Viral , Host-Pathogen Interactions/genetics , Humans , Nucleic Acid Conformation , Phylogeny , RNA Editing/physiology , RNA Viruses/classification , RNA, Viral/chemistry , RNA, Viral/genetics , SARS-CoV-2/chemistry , SARS-CoV-2/classification , Sequence Analysis, RNA , Transcription, Genetic/genetics , Uridine/genetics
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