ABSTRACT
OBJECTIVE: In human pathology, SARS-CoV-2 utilizes multiple molecular pathways to determine structural and biochemical changes within the different organs and cell types. The clinical picture of patients with COVID-19 is characterized by a very large spectrum. The reason for this variability has not been clarified yet, causing the inability to make a prognosis on the evolution of the disease. MATERIALS AND METHODS: PubMed search was performed focusing on the role of ACE 2 receptors in allowing the viral entry into cells, the role of ACE 2 downregulation in triggering the tissue pathology or in accelerating previous disease states, the role of increased levels of Angiotensin II in determining endothelial dysfunction and the enhanced vascular permeability, the role of the dysregulation of the renin angiotensin system in COVID-19 and the role of cytokine storm. RESULTS: The pathological changes induced by SARS-CoV-2 infection in the different organs, the correlations between the single cell types targeted by the virus in the different human organs and the clinical consequences, COVID-19 chronic pathologies in liver fibrosis, cardiac fibrosis and atrial arrhythmias, glomerulosclerosis and pulmonary fibrosis, due to the systemic fibroblast activation induced by angiotensin II are discussed. CONCLUSIONS: The main pathways involved showed different pathological changes in multiple tissues and the different clinical presentations. Even if ACE2 is the main receptor of SARS-CoV-2 and the main entry point into cells for the virus, ACE2 expression does not always explain the observed marked inter-individual variability in clinical presentation and outcome, evidencing the complexity of this disorder. The proper interpretation of the growing data available might allow to better classifying COVID-19 in human pathology.
Subject(s)
Angiotensin II/metabolism , Angiotensin-Converting Enzyme 2/metabolism , COVID-19/metabolism , Cardiomyopathies/metabolism , Cytokine Release Syndrome/metabolism , Endothelium, Vascular/physiopathology , Liver Cirrhosis/metabolism , Systemic Inflammatory Response Syndrome/metabolism , Thrombosis/metabolism , Angiotensin I/metabolism , Atrial Fibrillation/metabolism , Atrial Fibrillation/physiopathology , Blood Coagulation , COVID-19/pathology , COVID-19/physiopathology , Capillary Permeability , Cardiomyopathies/pathology , Cardiomyopathies/physiopathology , Cytokine Release Syndrome/physiopathology , Cytokines/metabolism , Fibroblasts/metabolism , Fibroblasts/pathology , Fibrosis , Humans , Liver Cirrhosis/pathology , Liver Cirrhosis/physiopathology , Myocarditis/metabolism , Myocarditis/pathology , Myocarditis/physiopathology , Receptors, Coronavirus/metabolism , Renin-Angiotensin System , SARS-CoV-2/metabolism , Systemic Inflammatory Response Syndrome/physiopathology , Thrombosis/physiopathology , Virus InternalizationABSTRACT
BACKGROUND: SARS-CoV-2 infection is associated with myocardial injury, but there is a paucity of experimental platforms for the condition.MethodsâandâResults:Human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) infected by SARS-CoV-2 for 3 days ceased beating and exhibited cytopathogenic changes with reduced viability. Active viral replication was evidenced by an increase in supernatant SARS-CoV-2 and the presence of SARS-CoV-2 nucleocaspid protein within hiPSC-CMs. Expressions of BNP, CXCL1, CXCL2, IL-6, IL-8 and TNF-α were upregulated, while ACE2 was downregulated. CONCLUSIONS: Our hiPSC-CM-based in-vitro SARS-CoV-2 myocarditis model recapitulated the cytopathogenic effects and cytokine/chemokine response. It could be exploited as a drug screening platform.
Subject(s)
Betacoronavirus/metabolism , Coronavirus Infections/complications , Induced Pluripotent Stem Cells/virology , Myocarditis/complications , Myocytes, Cardiac/virology , Pneumonia, Viral/complications , Angiotensin-Converting Enzyme 2 , Betacoronavirus/genetics , COVID-19 , Cell Survival , Cells, Cultured , Coronavirus Infections/metabolism , Coronavirus Infections/virology , Coronavirus Nucleocapsid Proteins , Cytokines/metabolism , Cytopathogenic Effect, Viral , Drug Evaluation, Preclinical/methods , Humans , Induced Pluripotent Stem Cells/metabolism , Myocarditis/metabolism , Myocarditis/virology , Myocytes, Cardiac/metabolism , Nucleocapsid Proteins/metabolism , Pandemics , Peptidyl-Dipeptidase A/metabolism , Phosphoproteins , Pneumonia, Viral/metabolism , Pneumonia, Viral/virology , Reverse Transcriptase Polymerase Chain Reaction , SARS-CoV-2 , Virus ReplicationABSTRACT
Importance: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can be documented in various tissues, but the frequency of cardiac involvement as well as possible consequences are unknown. Objective: To evaluate the presence of SARS-CoV-2 in the myocardial tissue from autopsy cases and to document a possible cardiac response to that infection. Design, Setting, and Participants: This cohort study used data from consecutive autopsy cases from Germany between April 8 and April 18, 2020. All patients had tested positive for SARS-CoV-2 in pharyngeal swab tests. Exposures: Patients who died of coronavirus disease 2019. Main Outcomes and Measures: Incidence of SARS-CoV-2 positivity in cardiac tissue as well as CD3+, CD45+, and CD68+ cells in the myocardium and gene expression of tumor necrosis growth factor α, interferon γ, chemokine ligand 5, as well as interleukin-6, -8, and -18. Results: Cardiac tissue from 39 consecutive autopsy cases were included. The median (interquartile range) age of patients was 85 (78-89) years, and 23 (59.0%) were women. SARS-CoV-2 could be documented in 24 of 39 patients (61.5%). Viral load above 1000 copies per µg RNA could be documented in 16 of 39 patients (41.0%). A cytokine response panel consisting of 6 proinflammatory genes was increased in those 16 patients compared with 15 patients without any SARS-CoV-2 in the heart. Comparison of 15 patients without cardiac infection with 16 patients with more than 1000 copies revealed no inflammatory cell infiltrates or differences in leukocyte numbers per high power field. Conclusions and Relevance: In this analysis of autopsy cases, viral presence within the myocardium could be documented. While a response to this infection could be reported in cases with higher virus load vs no virus infection, this was not associated with an influx of inflammatory cells. Future investigations should focus on evaluating the long-term consequences of this cardiac involvement.