SARS-CoV-2 Viral Genes Compromise Survival and Functions of Human Cardiomyocytes via Reducing Cellular ATP Level
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE171742 | GEO | 2023/05/10
REPOSITORIES: GEO
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Project description:Coronavirus disease 2019 (COVID-19) is a global pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). COVID-19 patients accompany with high frequencies of cardiac complications, which prominently contributed to the overall SARS-CoV-2-caused mortality. SARS-CoV-2 genome was reported to encode up to 14 genes. Currently, molecular mechanisms underlying SARS-CoV-2 viral gene-induced cardiac manifestations still remain elusive. Here, we overexpressed Orf9c, a SARS-CoV-2 encoded gene, in human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs). Multiple genome-wide analyses were performed to investigate the global impacts of Orf9c on hPSC-CMs. The mRNA-seq indicated stress-related signaling pathways, including cell death, immune and inflammation responses, activated by Orf9c. High-throughput proteomics and Co-immunoprecipitation mass spectrometry studies revealed the global influence of Orf9c on the proteome of hPSC-CMs and Orf9c-interactive protein network in hPSC-CMs. Orf9c overexpression elevated protein expressions of key factors essential for apoptosis while suppressing protein factors crucial for ATP synthesis. Further experimental validations confirmed that Orf9c overexpression induced prominent cell death, abnormal calcium handling and electrical properties, and significantly reduced cellular ATP level in hPSC-CMs. Finally, administration of two FDA-approved drugs, Ivermectin and Meclizine, were proven by our study to restore ATP level to prominently ameliorate Orf9c-induced cell death and electrical abnormalities of hPSC-CMs. Overall, we comprehensively manifest global responses of host human heart muscle cells to SARS-CoV-2 gene Orf9c, characterized molecular mechanisms underlying Orf9c-induced cardiac abnormalities, and explored potentially therapeutic approaches to ameliorate cardiac dysfunctions in COVID-19 patients.
2022-02-23 | GSE171370 | GEO
Project description:Coronavirus disease 2019 (COVID-19) is a viral pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). COVID-19 is predominantly defined by respiratory symptoms, but cardiac complications including arrhythmias, heart failure, and viral myocarditis are also prevalent. Although the systemic ischemic and inflammatory responses caused by COVID-19 can detrimentally affect cardiac function, the direct impact of SARS-CoV-2 infection on human cardiomyocytes is not well understood.
2020-06-19 | GSE150392 | GEO
Project description:For the assessment of host response dynamics to SARS-CoV and SARS-CoV-2 infections in human airway epithelial cells at ambient temperature corresponding to the upper or lower respiratory tract. We performed a temporal transcriptome analysis on human airway epithelial cell (hAEC) cultures infected with SARS-CoV and SARS-CoV-2, as well as uninfected hAEC cultures, incubated either at 33°C or 37°C. hAEC cultures were harvested at 24, 48 72, 96 hpi and processed for Bulk RNA Barcoding and sequencing (BRB-seq), which allows a rapid and sensitive genome-wide transcriptomic analysis in a highly multiplexed manner. Transcriptome data was obtained from a total of 7 biological donors for pairwise comparisons of SARS-CoV or SARS-CoV-2 virus-infected to unexposed hAEC cultures at respective time points and temperatures.
2020-11-27 | E-MTAB-9781 | biostudies-arrayexpress
Project description:A recombinant SARS-CoV lacking the envelope (E) protein is attenuated in vivo. Here we report that E protein PDZ-binding motif (PBM), a domain involved in protein-protein interactions, is a major virulence determinant in vivo. Elimination of SARS-CoV E protein PBM by using reverse genetics led to attenuated viruses (SARS-CoV-mutPBM) and to a reduction in the deleterious exacerbate immune response triggered during infection with the parental virus (SARS-CoV-wt). Cellular protein syntenin bound E protein PBM during SARS-CoV infection. Syntenin activates p38 MAPK leading to overexpression of inflammatory cytokines, and we have shown that active p38 MAPK was reduced in lungs of mice infected with SARS-CoVs lacking E protein PBM (SARS-CoV-mutPBM) as compared with the parental virus (SARS-CoV-wt), leading to a decreased expression of inflammatory cytokines and to viral attenuation. Therefore, E protein PBM is a virulence factor that activates pathogenic immune response most likely by using syntenin as a mediator of p38 MAPK induced inflammation. Three biological replicates were independently hybridized (one channel per slide) for each sample type (SARS-CoV-wt, SARS-CoV-mutPBM, Mock). Slides were Sure Print G3 Agilent 8x60K Mouse (G4852A-028005)
2014-10-31 | E-GEOD-52920 | biostudies-arrayexpress
Project description:Cardiovascular manifestations of COVID-19 include myocardial injury, heart failure, and myocarditis and are associated with long-term disability and mortality. SARS-CoV-2 RNA and antigens are found in the myocardium of COVID-19 patients, and human cardiomyocytes are susceptible to infection in cell or organoid cultures. While these observations raise the possibility that cardiomyocyte infection may contribute to the cardiac sequelae of COVID-19, a causal relationship between cardiomyocyte infection and myocardial dysfunction and pathology has not been established. Here, we generated a mouse model of cardiomyocyte-restricted infection by selectively expressing human angiotensin converting enzyme 2 (hACE2), the SARS-CoV-2 receptor, in cardiomyocytes. Inoculation of Myh6-Cre Rosa26LSL-hAce2 mice with SARS-CoV-2 resulted in viral replication within the heart, accumulation of macrophages, and moderate left ventricular (LV) systolic dysfunction. Cardiac pathology in this model was transient and resolved with viral clearance. Blockade of monocyte trafficking reduced myocardial viral replication and macrophage accumulation and suppressed the development of LV systolic dysfunction. These findings establish a mouse of model of SARS-CoV-2 cardiomyocyte infection that recapitulates features of cardiac dysfunctions of COVID-19 and suggests that both replication and resultant innate immune responses contribute to pathology
2023-12-31 | GSE239372 | GEO
Project description:SARS-CoV-2 Viral Genes Compromise Survival and Functions of Human Cardiomyocytes via Reducing Cellular ATP Level
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Project description:To explore the relationship between SARS-CoV-2 infection in different time before operation and postoperative main complications (mortality, main pulmonary and cardiovascular complications) 30 days after operation; To determine the best timing of surgery after SARS-CoV-2 infection.
| 12454 | ecrin-mdr-crc
Project description:The coronavirus disease 2019 (COVID-19), caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), remains to spread worldwide. COVID-19 is characterized by the striking high mortality in elderly; however, its mechanistic insights remain unclear. Systemic thrombosis has been highlighted in the pathogenesis of COVID-19, and lung microangiopathy in association with endothelial cells (ECs) injury has been reported by post-mortem analysis of the lungs. Here, we experimentally investigated the SARS-CoV-2 infection in cultured human ECs, and performed a comparative analysis for post-infection molecular events using early passage and replicative senescent ECs. We found that; 1) SARS-CoV-2 infects ECs but does not replicate and disappears in 72 hours without causing severe cell damage, 2) Senescent ECs are highly susceptible to SARS-CoV-2 infection, 3) SARS-CoV-2 infection alters various genes expression, which could cause EC dysfunctions, 4) More genes expression is affected in senescent ECs by SARS-CoV-2 infection than in early passage ECs, which might causes further exacerbated dysfunction in senescent ECs. These data suggest that sustained EC dysfunctions due to SARS-CoV-2 infection may contribute to the microangiopathy in the lungs, leading to deteriorated inflammation and thrombosis in COVID-19. Our data also suggest a possible causative role of EC senescence in the aggravated disease in elder COVID-19 patients.
2023-05-01 | GSE206677 | GEO
Project description:In this study, we investigated the effects of SARS-CoV-2 subunits on cardiomyocytes derived from human stem cells. The human induced pluripotent stem cells (hiPSCs) was differentiated into cardiomyocytes, and then were transfected with plasmids carrying different SARS-CoV-2 subunits. The cardiac functions, such as contractility and metabolic profiles, were investigated. We found the subunits 9B and S proteins has significantly adversed effects on the cardiac functions, compared to other groups. Thus, changes in transcriptome of cardiomyocytes (day30) after over expression of 9B, S for two days (on day 32) and two weeks (on day 45) were investigated by RNA-seq.
2023-02-02 | GSE202869 | GEO
Project description:To further investigate the underlying mechanisms of severe acute respiratory syndrome (SARS) pathogenesis and evaluate the therapeutic efficacy of potential drugs and vaccines it is necessary to use an animal model that is highly representative of the human condition in terms of respiratory anatomy, physiology and clinical sequelae. The ferret, Mustela putorius furo, supports SARS-CoV replication and displays many of the symptoms and pathological features seen in SARS-CoV-infected humans. We have recently established a SARS-CoV infection-challenge ferret platform for use in evaluating potential therapeutics to treat SARS. The main objective of the current study was to extend our previous results and identify early host immune responses upon infection and determine immune correlates of protection upon challenge with SARS-CoV in ferrets. Keywords: time course This study is a simple time course (58 day) examination of host responses in 35 SARS-CoV (TOR2) infected ferrets with the addition of a challenge inoculation of SARS CoV (TOR2) at day 29 post infection. Three mock-infected ferrets are included as negative controls. Due to the unavailability of ferret microarrays, Affymetrix Canine 2.0 oligonucleotide arrays were chosen following sequence analysis of our ferret cDNA library (~5000 clones) and demonstration of high levels of homology (>80%) between dog and ferret.
2013-05-28 | E-GEOD-11704 | biostudies-arrayexpress