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1.
J Virol ; 96(2): e0106321, 2022 01 26.
Article in English | MEDLINE | ID: covidwho-1476388

ABSTRACT

COVID-19 affects multiple organs. Clinical data from the Mount Sinai Health System show that substantial numbers of COVID-19 patients without prior heart disease develop cardiac dysfunction. How COVID-19 patients develop cardiac disease is not known. We integrated cell biological and physiological analyses of human cardiomyocytes differentiated from human induced pluripotent stem cells (hiPSCs) infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in the presence of interleukins (ILs) with clinical findings related to laboratory values in COVID-19 patients to identify plausible mechanisms of cardiac disease in COVID-19 patients. We infected hiPSC-derived cardiomyocytes from healthy human subjects with SARS-CoV-2 in the absence and presence of IL-6 and IL-1ß. Infection resulted in increased numbers of multinucleated cells. Interleukin treatment and infection resulted in disorganization of myofibrils, extracellular release of troponin I, and reduced and erratic beating. Infection resulted in decreased expression of mRNA encoding key proteins of the cardiomyocyte contractile apparatus. Although interleukins did not increase the extent of infection, they increased the contractile dysfunction associated with viral infection of cardiomyocytes, resulting in cessation of beating. Clinical data from hospitalized patients from the Mount Sinai Health System show that a significant portion of COVID-19 patients without history of heart disease have elevated troponin and interleukin levels. A substantial subset of these patients showed reduced left ventricular function by echocardiography. Our laboratory observations, combined with the clinical data, indicate that direct effects on cardiomyocytes by interleukins and SARS-CoV-2 infection might underlie heart disease in COVID-19 patients. IMPORTANCE SARS-CoV-2 infects multiple organs, including the heart. Analyses of hospitalized patients show that a substantial number without prior indication of heart disease or comorbidities show significant injury to heart tissue, assessed by increased levels of troponin in blood. We studied the cell biological and physiological effects of virus infection of healthy human iPSC-derived cardiomyocytes in culture. Virus infection with interleukins disorganizes myofibrils, increases cell size and the numbers of multinucleated cells, and suppresses the expression of proteins of the contractile apparatus. Viral infection of cardiomyocytes in culture triggers release of troponin similar to elevation in levels of COVID-19 patients with heart disease. Viral infection in the presence of interleukins slows down and desynchronizes the beating of cardiomyocytes in culture. The cell-level physiological changes are similar to decreases in left ventricular ejection seen in imaging of patients' hearts. These observations suggest that direct injury to heart tissue by virus can be one underlying cause of heart disease in COVID-19.


Subject(s)
COVID-19/immunology , Induced Pluripotent Stem Cells , Interleukin-10/immunology , Interleukin-1beta/immunology , Interleukin-6/immunology , Myocytes, Cardiac , Cells, Cultured , Humans , Induced Pluripotent Stem Cells/immunology , Induced Pluripotent Stem Cells/pathology , Induced Pluripotent Stem Cells/virology , Myocytes, Cardiac/immunology , Myocytes, Cardiac/pathology , Myocytes, Cardiac/virology
3.
Proc Natl Acad Sci U S A ; 118(16)2021 04 20.
Article in English | MEDLINE | ID: covidwho-1165017

ABSTRACT

Coronaviruses are adept at evading host antiviral pathways induced by viral double-stranded RNA, including interferon (IFN) signaling, oligoadenylate synthetase-ribonuclease L (OAS-RNase L), and protein kinase R (PKR). While dysregulated or inadequate IFN responses have been associated with severe coronavirus infection, the extent to which the recently emerged SARS-CoV-2 activates or antagonizes these pathways is relatively unknown. We found that SARS-CoV-2 infects patient-derived nasal epithelial cells, present at the initial site of infection; induced pluripotent stem cell-derived alveolar type 2 cells (iAT2), the major cell type infected in the lung; and cardiomyocytes (iCM), consistent with cardiovascular consequences of COVID-19 disease. Robust activation of IFN or OAS-RNase L is not observed in these cell types, whereas PKR activation is evident in iAT2 and iCM. In SARS-CoV-2-infected Calu-3 and A549ACE2 lung-derived cell lines, IFN induction remains relatively weak; however, activation of OAS-RNase L and PKR is observed. This is in contrast to Middle East respiratory syndrome (MERS)-CoV, which effectively inhibits IFN signaling and OAS-RNase L and PKR pathways, but is similar to mutant MERS-CoV lacking innate immune antagonists. Remarkably, OAS-RNase L and PKR are activated in MAVS knockout A549ACE2 cells, demonstrating that SARS-CoV-2 can induce these host antiviral pathways despite minimal IFN production. Moreover, increased replication and cytopathic effect in RNASEL knockout A549ACE2 cells implicates OAS-RNase L in restricting SARS-CoV-2. Finally, while SARS-CoV-2 fails to antagonize these host defense pathways, which contrasts with other coronaviruses, the IFN signaling response is generally weak. These host-virus interactions may contribute to the unique pathogenesis of SARS-CoV-2.


Subject(s)
Epithelial Cells/immunology , Epithelial Cells/virology , Immunity, Innate , Lung/pathology , Myocytes, Cardiac/immunology , Myocytes, Cardiac/virology , RNA, Double-Stranded/metabolism , SARS-CoV-2/immunology , A549 Cells , Endoribonucleases/metabolism , Humans , Middle East Respiratory Syndrome Coronavirus/immunology , Middle East Respiratory Syndrome Coronavirus/physiology , Nose/virology , Virus Replication , eIF-2 Kinase
4.
Eur J Immunol ; 51(4): 893-902, 2021 04.
Article in English | MEDLINE | ID: covidwho-986037

ABSTRACT

The aim of this study is to evaluate the blood level of anti-heart antibodies (AHA) and its correlation with clinical outcomes in patients with severe and moderate coronavirus disease 2019 (COVID-19). The study included 34 patients (23 males; mean age 60.2 ± 16.6 years) with COVID-19 pneumonia. Besides standard medical examination, the AHA blood levels were observed, including antinuclear antibodies, antiendothelial cell antibodies, anti-cardiomyocyte antibodies (AbC), anti-smooth muscle antibodies (ASMA), and cardiac conducting tissue antibodies. Median hospital length of stay was 14 [13; 18] days. AHA levels were increased in 25 (73.5%) patients. Significant correlation (p < 0.05) of AHA levels with cardiovascular manifestations (r = 0.459) was found. AbC levels correlated with pneumonia severity (r = 0.472), respiratory failure (r = 0.387), need for invasive ventilation (r = 0.469), chest pain (r = 0.374), low QRS voltage (r = 0.415), and levels of C-reactive protein (r = 0.360) and lactate dehydrogenase (r = 0.360). ASMA levels were found to correlate with atrial fibrillation (r = 0.414, p < 0.05). Antinuclear antibodies and AbC levels correlated with pericardial effusion (r = 0.721 and r = 0.745, respectively, p < 0.05). The lethality rate was 8.8%. AbC and ASMA levels correlated significantly with lethality (r = 0.363 and r = 0.426, respectively, p < 0.05) and were prognostically important. AHA can be considered as part of the systemic immune and inflammatory response in COVID-19. Its possible role in the inflammatory heart disease requires further investigation.


Subject(s)
Antibodies, Antinuclear/blood , COVID-19/immunology , COVID-19/pathology , Myocytes, Cardiac/immunology , SARS-CoV-2/immunology , Adult , Aged , Aged, 80 and over , Antibodies, Antinuclear/immunology , Atrial Fibrillation/pathology , Autoantibodies/blood , Autoantibodies/immunology , C-Reactive Protein/analysis , Endothelial Cells/immunology , Female , Heart/physiopathology , Humans , L-Lactate Dehydrogenase/blood , Male , Middle Aged , Muscle, Smooth/immunology , Myocardium/immunology , Pericardial Effusion/pathology , Young Adult
5.
Biomed Res Int ; 2020: 7413673, 2020.
Article in English | MEDLINE | ID: covidwho-619953

ABSTRACT

Some patients with coronavirus disease 2019 (COVID-19) show abnormal changes in laboratory myocardial injury markers, suggesting that patients with myocardial injury have a higher mortality rate than those without myocardial injury. This article reviews the possible mechanism of myocardial injury in patients with COVID-19. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) affects the patients with COVID-19 in aspects of direct infection of myocardial injury, specific binding to functional receptors on cardiomyocytes, and immune-mediated myocardial injury. During hospitalization, the monitoring of laboratory myocardial injury markers in patients of COVID-19 should be strengthened.


Subject(s)
Betacoronavirus , Coronavirus Infections/blood , Coronavirus Infections/complications , Heart Injuries/blood , Heart Injuries/etiology , Pneumonia, Viral/blood , Pneumonia, Viral/complications , Angiotensin-Converting Enzyme 2 , Biomarkers/blood , Biomarkers/metabolism , COVID-19 , Coronavirus Infections/metabolism , Cytokines/blood , Cytokines/immunology , Heart Injuries/metabolism , Humans , Inflammation Mediators/blood , Inflammation Mediators/immunology , Models, Cardiovascular , Models, Immunological , Myocytes, Cardiac/immunology , Myocytes, Cardiac/metabolism , Pandemics , Peptidyl-Dipeptidase A/metabolism , Pneumonia, Viral/metabolism , SARS-CoV-2
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