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1.
Life Sci ; 294: 120392, 2022 Apr 01.
Article in English | MEDLINE | ID: covidwho-1670857

ABSTRACT

The SARS coronavirus 2 (SARS CoV-2) causes Coronavirus Disease (COVID-19), is an emerging viral infection. SARS CoV-2 infects target cells by attaching to Angiotensin-Converting Enzyme (ACE2). SARS CoV-2 could cause cardiac damage in patients with severe COVID-19, as ACE2 is expressed in cardiac cells, including cardiomyocytes, pericytes, and fibroblasts, and coronavirus could directly infect these cells. Cardiovascular disorders are the most frequent comorbidity found in COVID-19 patients. Immune cells such as monocytes, macrophages, and T cells may produce inflammatory cytokines and chemokines that contribute to COVID-19 pathogenesis if their functions are uncontrolled. This causes a cytokine storm in COVID-19 patients, which has been associated with cardiac damage. Tregs are a subset of immune cells that regulate immune and inflammatory responses. Tregs suppress inflammation and improve cardiovascular function through a variety of mechanisms. This is an exciting research area to explore the cellular, molecular, and immunological mechanisms related to reducing risks of cardiovascular complications in severe COVID-19. This review evaluated whether Tregs can affect COVID-19-related cardiovascular complications, as well as the mechanisms through which Tregs act.


Subject(s)
COVID-19/immunology , Cardiovascular Diseases/immunology , Cardiovascular Diseases/prevention & control , SARS-CoV-2 , T-Lymphocytes, Regulatory/physiology , Adoptive Transfer , Animals , Cardiovascular Diseases/virology , Cytokine Release Syndrome/immunology , Cytokine Release Syndrome/prevention & control , Humans , Inflammation/immunology , T-Lymphocytes, Regulatory/immunology
2.
Int J Mol Sci ; 23(2)2022 Jan 15.
Article in English | MEDLINE | ID: covidwho-1631216

ABSTRACT

Angiotensin II receptor type 1 (AT1R) and endothelin-1 receptor type A (ETAR) are G-protein-coupled receptors (GPCRs) expressed on the surface of a great variety of cells: immune cells, vascular smooth cells, endothelial cells, and fibroblasts express ETAR and AT1R, which are activated by endothelin 1 (ET1) and angiotensin II (AngII), respectively. Certain autoantibodies are specific for these receptors and can regulate their function, thus being known as functional autoantibodies. The function of these antibodies is similar to that of natural ligands, and it involves not only vasoconstriction, but also the secretion of proinflammatory cytokines (such as interleukin-6 (IL6), IL8 and TNF-α), collagen production by fibroblasts, and reactive oxygen species (ROS) release by fibroblasts and neutrophils. The role of autoantibodies against AT1R and ETAR (AT1R-AAs and ETAR-AAs, respectively) is well described in the pathogenesis of many medical conditions (e.g., systemic sclerosis (SSc) and SSc-associated pulmonary hypertension, cystic fibrosis, and allograft dysfunction), but their implications in cardiovascular diseases are still unclear. This review summarizes the current evidence regarding the effects of AT1R-AAs and ETAR-AAs in cardiovascular pathologies, highlighting their roles in heart transplantation and mechanical circulatory support, preeclampsia, and acute coronary syndromes.


Subject(s)
Autoantibodies/metabolism , Cardiovascular Diseases/immunology , Receptor, Angiotensin, Type 1/immunology , Receptor, Endothelin A/immunology , Cardiovascular Diseases/metabolism , Cardiovascular Diseases/pathology , Collagen/metabolism , Humans , Interleukin-6/metabolism , Interleukin-8/metabolism , Reactive Oxygen Species/metabolism , Receptor, Angiotensin, Type 1/metabolism , Tumor Necrosis Factor-alpha/metabolism
3.
J Cell Mol Med ; 26(2): 274-286, 2022 01.
Article in English | MEDLINE | ID: covidwho-1566302

ABSTRACT

Based on the recent reports, cardiovascular events encompass a large portion of the mortality caused by the COVID-19 pandemic, which drawn cardiologists into the management of the admitted ill patients. Given that common laboratory values may provide key insights into the illness caused by the life-threatening SARS-CoV-2 virus, it would be more helpful for screening, clinical management and on-time therapeutic strategies. Commensurate with these issues, this review article aimed to discuss the dynamic changes of the common laboratory parameters during COVID-19 and their association with cardiovascular diseases. Besides, the values that changed in the early stage of the disease were considered and monitored during the recovery process. The time required for returning biomarkers to basal levels was also discussed. Finally, of particular interest, we tended to abridge the latest updates regarding the cardiovascular biomarkers as prognostic and diagnostic criteria to determine the severity of COVID-19.


Subject(s)
COVID-19/blood , Cardiovascular Diseases/blood , Cardiovascular System/metabolism , SARS-CoV-2/pathogenicity , Biomarkers/blood , COVID-19/complications , COVID-19/diagnosis , COVID-19/immunology , Cardiovascular Diseases/complications , Cardiovascular Diseases/diagnosis , Cardiovascular Diseases/immunology , Cardiovascular System/pathology , Cardiovascular System/virology , Chemokine CCL2/blood , Creatine Kinase, MB Form/blood , Fibrin Fibrinogen Degradation Products/metabolism , Homocysteine/blood , Humans , Interferon-gamma/blood , Interleukin-6/blood , L-Lactate Dehydrogenase/blood , Natriuretic Peptide, Brain/blood , Peptide Fragments/blood , Prognosis , SARS-CoV-2/growth & development , SARS-CoV-2/immunology , Troponin I/blood , Troponin T/blood , Tumor Necrosis Factor-alpha/blood
4.
Int J Mol Sci ; 22(18)2021 Sep 13.
Article in English | MEDLINE | ID: covidwho-1409702

ABSTRACT

The coronavirus disease 2019 (COVID-19) pandemic with high infectivity and mortality has caused severe social and economic impacts worldwide. Growing reports of COVID-19 patients with multi-organ damage indicated that severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) may also disturb the cardiovascular system. Herein, we used human induced pluripotent stem cell (iPSC)-derived cardiomyocytes (iCMs) as the in vitro platform to examine the consequence of SARS-CoV2 infection on iCMs. Differentiated iCMs expressed the primary SARS-CoV2 receptor angiotensin-converting enzyme-II (ACE2) and the transmembrane protease serine type 2 (TMPRSS2) receptor suggesting the susceptibility of iCMs to SARS-CoV2. Following the infection of iCMs with SARS-CoV2, the viral nucleocapsid (N) protein was detected in the host cells, demonstrating the successful infection. Bioinformatics analysis revealed that the SARS-CoV2 infection upregulates several inflammation-related genes, including the proinflammatory cytokine tumor necrosis factor-α (TNF-α). The pretreatment of iCMs with TNF-α for 24 h, significantly increased the expression of ACE2 and TMPRSS2, SASR-CoV2 entry receptors. The TNF-α pretreatment enhanced the entry of GFP-expressing SARS-CoV2 pseudovirus into iCMs, and the neutralization of TNF-α ameliorated the TNF-α-enhanced viral entry. Collectively, SARS-CoV2 elevated TNF-α expression, which in turn enhanced the SARS-CoV2 viral entry. Our findings suggest that, TNF-α may participate in the cytokine storm and aggravate the myocardial damage in COVID-19 patients.


Subject(s)
COVID-19/complications , Cardiovascular Diseases/immunology , Cytokine Release Syndrome/immunology , SARS-CoV-2/immunology , Tumor Necrosis Factor-alpha/metabolism , Angiotensin-Converting Enzyme 2/metabolism , COVID-19/immunology , COVID-19/pathology , COVID-19/virology , Cardiovascular Diseases/virology , Cell Differentiation , Cell Line , Computational Biology , Coronavirus Nucleocapsid Proteins/metabolism , Cytokine Release Syndrome/pathology , Cytokine Release Syndrome/virology , Humans , Induced Pluripotent Stem Cells , Myocardium/cytology , Myocardium/immunology , Myocardium/pathology , Myocytes, Cardiac/metabolism , Myocytes, Cardiac/virology , Phosphoproteins/metabolism , SARS-CoV-2/metabolism , SARS-CoV-2/pathogenicity , Serine Endopeptidases/metabolism , Tumor Necrosis Factor-alpha/antagonists & inhibitors , Up-Regulation/immunology , Virus Internalization/drug effects
5.
Stem Cell Rev Rep ; 17(6): 2107-2119, 2021 12.
Article in English | MEDLINE | ID: covidwho-1345193

ABSTRACT

The virus responsible for coronavirus disease 2019 (COVID-19), severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has infected over 190 million people to date, causing a global pandemic. SARS-CoV-2 relies on binding of its spike glycoprotein to angiotensin-converting enzyme 2 (ACE2) for infection. In addition to fever, cough, and shortness of breath, severe cases of SARS-CoV-2 infection may result in the rapid overproduction of pro-inflammatory cytokines. This overactive immune response is known as a cytokine storm, which leads to several serious clinical manifestations such as acute respiratory distress syndrome and myocardial injury. Cardiovascular disorders such as acute coronary syndrome (ACS) and heart failure not only enhance disease progression at the onset of infection, but also arise in hospitalized patients with COVID-19. Tissue-specific differentiated cells and organoids derived from human pluripotent stem cells (hPSCs) serve as an excellent model to address how SARS-CoV-2 damages the lungs and the heart. In this review, we summarize the molecular basis of SARS-CoV-2 infection and the current clinical perspectives of the bidirectional relationship between the cardiovascular system and viral progression. Furthermore, we also address the utility of hPSCs as a dynamic model for SARS-CoV-2 research and clinical translation.


Subject(s)
COVID-19/virology , Cardiovascular System/virology , Pluripotent Stem Cells/virology , COVID-19/immunology , Cardiovascular Diseases/immunology , Cardiovascular Diseases/virology , Cardiovascular System/immunology , Cytokine Release Syndrome/immunology , Cytokine Release Syndrome/virology , Humans , Lung/immunology , Lung/virology , Pandemics/prevention & control , Pluripotent Stem Cells/immunology , SARS-CoV-2/pathogenicity
6.
Cell ; 184(11): 2797-2801, 2021 05 27.
Article in English | MEDLINE | ID: covidwho-1241746

ABSTRACT

The COVID-19 pandemic has highlighted structural inequalities and racism promoting health disparities among communities of color. Taking cardiovascular disease as an example, we provide a framework for multidisciplinary efforts leveraging translational and epidemiologic approaches to decode the biological impacts of inequalities and racism and develop targeted interventions that promote health equity.


Subject(s)
COVID-19/epidemiology , Health Equity , Health Promotion/methods , Racism , Stress, Physiological/immunology , COVID-19/immunology , COVID-19/metabolism , COVID-19/psychology , Cardiovascular Diseases/epidemiology , Cardiovascular Diseases/immunology , Cardiovascular Diseases/metabolism , Cardiovascular Diseases/psychology , Gene Expression Regulation/genetics , Gene Expression Regulation/immunology , Gene Expression Regulation/physiology , Humans , Hypothalamo-Hypophyseal System/immunology , Hypothalamo-Hypophyseal System/physiology , Racism/psychology , Risk Factors , Sympathetic Nervous System/immunology , Sympathetic Nervous System/physiology
7.
Int Arch Allergy Immunol ; 182(8): 765-774, 2021.
Article in English | MEDLINE | ID: covidwho-1234321

ABSTRACT

PURPOSE: The aim of this study is to evaluate the frequency of cardiac involvement in patients with coronavirus disease 2019 (COVID-19), possible immune mechanisms of myocardial injury, and the place of cardiovascular pathology among other prognostic factors. METHODS: The study included 86 patients (48 male, 60.2 ± 16.6 years) with COVID-19. In addition to common investigation, examination of troponin T (n = 18) and anti-heart antibodies (AHA, n = 34) were used. The average hospital period was 14 [12; 18] days. RESULTS: The incidence of cardiovascular disease and symptoms was 45.3%. Arrhythmias, heart failure, low-QRS voltage, repolarization disorders, and pericardial effusion were the typical for coronavirus cardiac injury. The level of AHA was increased in 73.5%. Significant (p < 0.05) correlations of AHA level with inflammatory activity, pneumonia, respiratory failure, cardiac symptoms, and death were found. D-dimer >0.5 µg/mL had a sensitivity of 79.2% and specificity of 60% in the prediction of cardiovascular manifestations. Cardiac failure was one of the causes of death in 3/8 patients (37.5%). Lethality in the presence of cardiovascular pathology was 17.9 versus 2.2% without it, p < 0.05. The most powerful prognostic model includes age, diabetes, oxygen therapy volume, maximum leukocyte level, C-reactive protein, and D-dimer (correlation coefficient 0.871, p < 0.001). The model with only age, diabetes, and cardiovascular disease included also had predictive power (correlation coefficient 0.568, p < 0.001). CONCLUSIONS: The cardiovascular pathology is frequent in patients with COVID-19 and strong correlates with the D-dimer. It indicates the high significance of prothrombotic and ischemic mechanisms. High AHA levels may reflect an inflammatory heart injury. The cardiovascular pathology is associated with higher lethality.


Subject(s)
COVID-19/immunology , Cardiovascular Diseases/immunology , Myocardium/immunology , Pneumonia/immunology , SARS-CoV-2/physiology , Aged , Autoantibodies/blood , COVID-19/diagnosis , COVID-19/epidemiology , Cardiovascular Diseases/diagnosis , Cardiovascular Diseases/epidemiology , Female , Humans , Incidence , Inflammation , Male , Middle Aged , Models, Statistical , Myocardium/metabolism , Myocardium/pathology , Pneumonia/epidemiology , Prognosis , Russia/epidemiology , Troponin T/metabolism
8.
Clin Immunol ; 227: 108733, 2021 06.
Article in English | MEDLINE | ID: covidwho-1198654

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for many pathological processes, including altered vascular disease development, dysfunctional thrombosis and a heightened inflammatory response. However, there is limited work to determine the underlying cellular responses induced by exposure to SARS-CoV-2 structural proteins. Thus, our objective was to investigate how human arterial adventitial fibroblasts inflammation, thrombosis and diabetic disease markers are altered in response to Spike, Nucleocapsid and Membrane-Envelope proteins. We hypothesized that after a short-term exposure to SARS-CoV-2 proteins, adventitial fibroblasts would have a higher expression of inflammatory, thrombotic and diabetic proteins, which would support a mechanism for altered vascular disease progression. After incubation, the expression of gC1qR, ICAM-1, tissue factor, RAGE and GLUT-4 was significantly up-regulated. In general, the extent of expression was different for each SARS-CoV-2 protein, suggesting that SARS-CoV-2 proteins interact with cells through different mechanisms. Thus, SARS-CoV-2 protein interaction with vascular cells may regulate vascular disease responses.


Subject(s)
COVID-19/immunology , Cardiovascular Diseases/virology , Diabetes Mellitus/virology , Fibroblasts/metabolism , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/immunology , Thrombosis/virology , Aorta/cytology , Aorta/metabolism , Cardiovascular Diseases/complications , Cardiovascular Diseases/immunology , Cardiovascular Diseases/metabolism , Carrier Proteins/metabolism , Cell Survival/immunology , Cell Survival/physiology , Complement System Proteins/immunology , Coronavirus Envelope Proteins/immunology , Coronavirus Nucleocapsid Proteins/immunology , Coronavirus Nucleocapsid Proteins/metabolism , Diabetes Mellitus/metabolism , Glucose Transporter Type 4/metabolism , Humans , Inflammation/metabolism , Inflammation/virology , Intercellular Adhesion Molecule-1/metabolism , Mitochondrial Proteins/metabolism , Receptor for Advanced Glycation End Products/metabolism , Thrombosis/complications , Thrombosis/metabolism
9.
Genome Med ; 13(1): 66, 2021 04 21.
Article in English | MEDLINE | ID: covidwho-1197350

ABSTRACT

BACKGROUND: The large airway epithelial barrier provides one of the first lines of defense against respiratory viruses, including SARS-CoV-2 that causes COVID-19. Substantial inter-individual variability in individual disease courses is hypothesized to be partially mediated by the differential regulation of the genes that interact with the SARS-CoV-2 virus or are involved in the subsequent host response. Here, we comprehensively investigated non-genetic and genetic factors influencing COVID-19-relevant bronchial epithelial gene expression. METHODS: We analyzed RNA-sequencing data from bronchial epithelial brushings obtained from uninfected individuals. We related ACE2 gene expression to host and environmental factors in the SPIROMICS cohort of smokers with and without chronic obstructive pulmonary disease (COPD) and replicated these associations in two asthma cohorts, SARP and MAST. To identify airway biology beyond ACE2 binding that may contribute to increased susceptibility, we used gene set enrichment analyses to determine if gene expression changes indicative of a suppressed airway immune response observed early in SARS-CoV-2 infection are also observed in association with host factors. To identify host genetic variants affecting COVID-19 susceptibility in SPIROMICS, we performed expression quantitative trait (eQTL) mapping and investigated the phenotypic associations of the eQTL variants. RESULTS: We found that ACE2 expression was higher in relation to active smoking, obesity, and hypertension that are known risk factors of COVID-19 severity, while an association with interferon-related inflammation was driven by the truncated, non-binding ACE2 isoform. We discovered that expression patterns of a suppressed airway immune response to early SARS-CoV-2 infection, compared to other viruses, are similar to patterns associated with obesity, hypertension, and cardiovascular disease, which may thus contribute to a COVID-19-susceptible airway environment. eQTL mapping identified regulatory variants for genes implicated in COVID-19, some of which had pheWAS evidence for their potential role in respiratory infections. CONCLUSIONS: These data provide evidence that clinically relevant variation in the expression of COVID-19-related genes is associated with host factors, environmental exposures, and likely host genetic variation.


Subject(s)
Bronchi , COVID-19/genetics , Respiratory Mucosa , SARS-CoV-2 , Adult , Aged , Aged, 80 and over , Angiotensin-Converting Enzyme 2/genetics , Asthma/genetics , COVID-19/immunology , Cardiovascular Diseases/genetics , Cardiovascular Diseases/immunology , Gene Expression , Genetic Variation , Humans , Middle Aged , Obesity/genetics , Obesity/immunology , Pulmonary Disease, Chronic Obstructive/genetics , Quantitative Trait Loci , Risk Factors , Smoking/genetics
10.
Cells ; 10(4)2021 04 16.
Article in English | MEDLINE | ID: covidwho-1194613

ABSTRACT

Coronavirus disease 2019 (COVID-19) is the most devastating infectious disease in the 21st century with more than 2 million lives lost in less than a year. The activation of inflammasome in the host infected by SARS-CoV-2 is highly related to cytokine storm and hypercoagulopathy, which significantly contribute to the poor prognosis of COVID-19 patients. Even though many studies have shown the host defense mechanism induced by inflammasome against various viral infections, mechanistic interactions leading to downstream cellular responses and pathogenesis in COVID-19 remain unclear. The SARS-CoV-2 infection has been associated with numerous cardiovascular disorders including acute myocardial injury, myocarditis, arrhythmias, and venous thromboembolism. The inflammatory response triggered by the activation of NLRP3 inflammasome under certain cardiovascular conditions resulted in hyperinflammation or the modulation of angiotensin-converting enzyme 2 signaling pathways. Perturbations of several target cells and tissues have been described in inflammasome activation, including pneumocytes, macrophages, endothelial cells, and dendritic cells. The interplay between inflammasome activation and hypercoagulopathy in COVID-19 patients is an emerging area to be further addressed. Targeted therapeutics to suppress inflammasome activation may have a positive effect on the reduction of hyperinflammation-induced hypercoagulopathy and cardiovascular disorders occurring as COVID-19 complications.


Subject(s)
COVID-19/complications , Cardiovascular Diseases/etiology , Inflammasomes/immunology , Thrombophilia/etiology , Animals , COVID-19/immunology , COVID-19/pathology , Cardiovascular Diseases/immunology , Cardiovascular Diseases/pathology , Humans , NLR Family, Pyrin Domain-Containing 3 Protein/immunology , SARS-CoV-2/immunology , Thrombophilia/immunology , Thrombophilia/pathology
11.
Am J Respir Cell Mol Biol ; 65(1): 13-21, 2021 07.
Article in English | MEDLINE | ID: covidwho-1166652

ABSTRACT

Coronavirus disease (COVID-19), the clinical syndrome caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is currently a global health pandemic with substantial morbidity and mortality. COVID-19 has cast a shadow on nearly every aspect of society, straining health systems and economies across the world. Although it is widely accepted that a close relationship exists between obesity, cardiovascular disease, and metabolic disorders on infection, we are only beginning to understand ways in which the immunological sequelae of obesity functions as a predisposing factor related to poor clinical outcomes in COVID-19. As both the innate and adaptive immune systems are each primed by obesity, the alteration of key pathways results in both an immunosuppressed and hyperinflammatory state. The present review will discuss the cellular and molecular immunology of obesity in the context of its role as a risk factor for severe COVID-19, discuss the role of cytokine storm, and draw parallels to prior viral epidemics such as severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS), and 2009 H1N1.


Subject(s)
COVID-19 , Cardiovascular Diseases , Cytokine Release Syndrome , Obesity , SARS-CoV-2 , COVID-19/immunology , COVID-19/metabolism , COVID-19/mortality , Cardiovascular Diseases/immunology , Cardiovascular Diseases/metabolism , Cardiovascular Diseases/mortality , Critical Illness , Cytokine Release Syndrome/immunology , Cytokine Release Syndrome/metabolism , Cytokine Release Syndrome/mortality , Cytokine Release Syndrome/virology , Disease-Free Survival , Humans , Obesity/immunology , Obesity/metabolism , Obesity/mortality , Obesity/virology , SARS-CoV-2/immunology , SARS-CoV-2/metabolism , Survival Rate
12.
Elife ; 102021 03 23.
Article in English | MEDLINE | ID: covidwho-1146275

ABSTRACT

Numerous reports of vascular events after an initial recovery from COVID-19 form our impetus to investigate the impact of COVID-19 on vascular health of recovered patients. We found elevated levels of circulating endothelial cells (CECs), a biomarker of vascular injury, in COVID-19 convalescents compared to healthy controls. In particular, those with pre-existing conditions (e.g., hypertension, diabetes) had more pronounced endothelial activation hallmarks than non-COVID-19 patients with matched cardiovascular risk. Several proinflammatory and activated T lymphocyte-associated cytokines sustained from acute infection to recovery phase, which correlated positively with CEC measures, implicating cytokine-driven endothelial dysfunction. Notably, we found higher frequency of effector T cells in our COVID-19 convalescents compared to healthy controls. The activation markers detected on CECs mapped to counter receptors found primarily on cytotoxic CD8+ T cells, raising the possibility of cytotoxic effector cells targeting activated endothelial cells. Clinical trials in preventive therapy for post-COVID-19 vascular complications may be needed.


Subject(s)
COVID-19/complications , Cardiovascular Diseases/etiology , Endothelium, Vascular/pathology , Lymphocyte Activation , Adult , Aged , COVID-19/immunology , COVID-19/pathology , Cardiovascular Diseases/immunology , Cardiovascular Diseases/pathology , Cytokines/immunology , Endothelial Cells/immunology , Endothelial Cells/pathology , Endothelium, Vascular/immunology , Female , Humans , Male , Middle Aged , Risk Factors
13.
JCI Insight ; 6(6)2021 03 22.
Article in English | MEDLINE | ID: covidwho-1097059

ABSTRACT

Comorbid medical illnesses, such as obesity and diabetes, are associated with more severe COVID-19, hospitalization, and death. However, the role of the immune system in mediating these clinical outcomes has not been determined. We used multiparameter flow cytometry and systems serology to comprehensively profile the functions of T cells and antibodies targeting spike, nucleocapsid, and envelope proteins in a convalescent cohort of COVID-19 subjects who were either hospitalized (n = 20) or not hospitalized (n = 40). To avoid confounding, subjects were matched by age, sex, ethnicity, and date of symptom onset. Surprisingly, we found that the magnitude and functional breadth of virus-specific CD4+ T cell and antibody responses were consistently higher among hospitalized subjects, particularly those with medical comorbidities. However, an integrated analysis identified more coordination between polyfunctional CD4+ T cells and antibodies targeting the S1 domain of spike among subjects who were not hospitalized. These data reveal a functionally diverse and coordinated response between T cells and antibodies targeting SARS-CoV-2, which is reduced in the presence of comorbid illnesses that are known risk factors for severe COVID-19.


Subject(s)
Antibodies, Viral/physiology , CD4-Positive T-Lymphocytes/physiology , COVID-19/virology , Hospitalization , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus , Virion , Adult , Aged , Antibodies, Neutralizing/metabolism , Antibodies, Neutralizing/physiology , Antibodies, Viral/metabolism , CD4-Positive T-Lymphocytes/metabolism , COVID-19/epidemiology , COVID-19/immunology , Cardiovascular Diseases/epidemiology , Cardiovascular Diseases/immunology , Comorbidity , Diabetes Mellitus/epidemiology , Diabetes Mellitus/immunology , Female , Humans , Immunity, Humoral , Male , Middle Aged , Nucleocapsid , Severity of Illness Index , Viral Envelope , Viral Proteins , Young Adult
16.
Am J Physiol Heart Circ Physiol ; 320(1): H296-H304, 2021 01 01.
Article in English | MEDLINE | ID: covidwho-961166

ABSTRACT

Biological sex is increasingly recognized as a critical determinant of health and disease, particularly relevant to the topical COVID-19 pandemic caused by the SARS-CoV-2 coronavirus. Epidemiological data and observational reports from both the original SARS epidemic and the most recent COVID-19 pandemic have a common feature: males are more likely to exhibit enhanced disease severity and mortality than females. Sex differences in cardiovascular disease and COVID-19 share mechanistic foundations, namely, the involvement of both the innate immune system and the canonical renin-angiotensin system (RAS). Immunological differences suggest that females mount a rapid and aggressive innate immune response, and the attenuated antiviral response in males may confer enhanced susceptibility to severe disease. Furthermore, the angiotensin-converting enzyme 2 (ACE2) is involved in disease pathogenesis in cardiovascular disease and COVID-19, either to serve as a protective mechanism by deactivating the RAS or as the receptor for viral entry, respectively. Loss of membrane ACE2 and a corresponding increase in plasma ACE2 are associated with worsened cardiovascular disease outcomes, a mechanism attributed to a disintegrin and metalloproteinase (ADAM17). SARS-CoV-2 infection also leads to ADAM17 activation, a positive feedback cycle that exacerbates ACE2 loss. Therefore, the relationship between cardiovascular disease and COVID-19 is critically dependent on the loss of membrane ACE2 by ADAM17-mediated proteolytic cleavage. This article explores potential mechanisms involved in COVID-19 that may contribute to sex-specific susceptibility focusing on the innate immune system and the RAS, namely, genetics and sex hormones. Finally, we highlight here the added challenges of gender in the COVID-19 pandemic.


Subject(s)
Adaptive Immunity/immunology , Androgens/immunology , Angiotensin-Converting Enzyme 2/genetics , COVID-19/immunology , Estrogens/immunology , Immunity, Innate/immunology , Receptors, Coronavirus/genetics , ADAM17 Protein/metabolism , Adaptive Immunity/genetics , Androgens/metabolism , Angiotensin-Converting Enzyme 2/metabolism , COVID-19/genetics , COVID-19/metabolism , COVID-19/mortality , Cardiovascular Diseases/genetics , Cardiovascular Diseases/immunology , Estrogens/metabolism , Female , Genes, X-Linked/genetics , Genes, X-Linked/immunology , Humans , Immunity, Innate/genetics , Male , Promoter Regions, Genetic , Receptors, Coronavirus/metabolism , Renin-Angiotensin System/genetics , Renin-Angiotensin System/immunology , Response Elements/genetics , SARS-CoV-2/metabolism , Severity of Illness Index , Sex Characteristics , Sex Factors , X Chromosome Inactivation
17.
J Immunol Res ; 2020: 8632048, 2020.
Article in English | MEDLINE | ID: covidwho-961172

ABSTRACT

Novel coronavirus disease 2019 (COVID-19) causes pulmonary and cardiovascular disorders and has become a worldwide emergency. Myocardial injury can be caused by direct or indirect damage, particularly mediated by a cytokine storm, a disordered immune response that can cause myocarditis, abnormal coagulation, arrhythmia, acute coronary syndrome, and myocardial infarction. The present review focuses on the mechanisms of this viral infection, cardiac biomarkers, consequences, and the possible therapeutic role of purinergic and adenosinergic signalling systems. In particular, we focus on the interaction of the extracellular nucleotide adenosine triphosphate (ATP) with its receptors P2X1, P2X4, P2X7, P2Y1, and P2Y2 and of adenosine (Ado) with A2A and A3 receptors, as well as their roles in host immune responses. We suggest that receptors of purinergic signalling could be ideal candidates for pharmacological targeting to protect against myocardial injury caused by a cytokine storm in COVID-19, in order to reduce systemic inflammatory damage to cells and tissues, preventing the progression of the disease by modulating the immune response and improving patient quality of life.


Subject(s)
Adenosine Triphosphate/metabolism , COVID-19/immunology , Cardiovascular Diseases/virology , Receptors, Purinergic/metabolism , SARS-CoV-2 , Adenosine A2 Receptor Agonists/pharmacology , COVID-19/drug therapy , COVID-19/metabolism , Cardiovascular Diseases/immunology , Cardiovascular Diseases/physiopathology , Cytokines/metabolism , Humans , Myocardial Ischemia/immunology , Myocardial Ischemia/physiopathology , Myocardial Ischemia/virology , Pandemics , Purinergic Antagonists/pharmacology , Receptor, Adenosine A2A/metabolism , Receptor, Adenosine A3/metabolism , Signal Transduction/drug effects , Signal Transduction/immunology
18.
Front Immunol ; 11: 570681, 2020.
Article in English | MEDLINE | ID: covidwho-918135

ABSTRACT

Influenza virus infection causes 3-5 million cases of severe illness and 250,000-500,000 deaths worldwide annually. Although pneumonia is the most common complication associated with influenza, there are several reports demonstrating increased risk for cardiovascular diseases. Several clinical case reports, as well as both prospective and retrospective studies, have shown that influenza can trigger cardiovascular events including myocardial infarction (MI), myocarditis, ventricular arrhythmia, and heart failure. A recent study has demonstrated that influenza-infected patients are at highest risk of having MI during the first seven days of diagnosis. Influenza virus infection induces a variety of pro-inflammatory cytokines and chemokines and recruitment of immune cells as part of the host immune response. Understanding the cellular and molecular mechanisms involved in influenza-associated cardiovascular diseases will help to improve treatment plans. This review discusses the direct and indirect effects of influenza virus infection on triggering cardiovascular events. Further, we discussed the similarities and differences in epidemiological and pathogenic mechanisms involved in cardiovascular events associated with coronavirus disease 2019 (COVID-19) compared to influenza infection.


Subject(s)
COVID-19/immunology , Cardiovascular Diseases/immunology , Orthomyxoviridae/physiology , SARS-CoV-2/physiology , Animals , COVID-19/genetics , COVID-19/virology , Cardiovascular Diseases/virology , Cytokines/genetics , Cytokines/immunology , Humans , Influenza, Human/genetics , Influenza, Human/immunology , Influenza, Human/virology , Orthomyxoviridae/genetics , SARS-CoV-2/genetics
19.
Thromb Haemost ; 120(12): 1629-1641, 2020 Dec.
Article in English | MEDLINE | ID: covidwho-894451

ABSTRACT

The global coronavirus disease 2019 (COVID-19) pandemic has deranged the recent history of humankind, afflicting more than 27 million individuals to date. While the majority of COVID-19 patients recuperate, a considerable number of patients develop severe complications. Bilateral pneumonia constitutes the hallmark of severe COVID-19 disease but an involvement of other organ systems, namely the cardiovascular system, kidneys, liver, and central nervous system, occurs in at least half of the fatal COVID-19 cases. Besides respiratory failure requiring ventilation, patients with severe COVID-19 often display manifestations of systemic inflammation and thrombosis as well as diffuse microvascular injury observed postmortem. In this review, we survey the mechanisms that may explain how viral entry and activation of endothelial cells by severe acute respiratory syndrome coronavirus 2 can give rise to a series of events including systemic inflammation, thrombosis, and microvascular dysfunction. This pathophysiological scenario may be particularly harmful in patients with overt cardiovascular disease and may drive the fatal aspects of COVID-19. We further shed light on the role of the renin-angiotensin aldosterone system and its inhibitors in the context of COVID-19 and discuss the potential impact of antiviral and anti-inflammatory treatment options. Acknowledging the comorbidities and potential organ injuries throughout the course of severe COVID-19 is crucial in the clinical management of patients affecting treatment approaches and recovery rate.


Subject(s)
COVID-19/immunology , Cardiovascular Diseases/immunology , Inflammation/immunology , Renin-Angiotensin System , SARS-CoV-2/physiology , COVID-19/epidemiology , Cardiovascular Diseases/epidemiology , Hemostasis , Humans , Immunity , Microcirculation , Pandemics , Thrombosis
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