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1.
Lab Chip ; 22(6): 1171-1186, 2022 03 15.
Article in English | MEDLINE | ID: covidwho-1684131

ABSTRACT

Coronavirus disease 2019 (COVID-19) was primarily identified as a novel disease causing acute respiratory syndrome. However, as the pandemic progressed various cases of secondary organ infection and damage by severe respiratory syndrome coronavirus 2 (SARS-CoV-2) have been reported, including a breakdown of the vascular barrier. As SARS-CoV-2 gains access to blood circulation through the lungs, the virus is first encountered by the layer of endothelial cells and immune cells that participate in host defense. Here, we developed an approach to study SARS-CoV-2 infection using vasculature-on-a-chip. We first modeled the interaction of virus alone with the endothelialized vasculature-on-a-chip, followed by the studies of the interaction of the virus exposed-endothelial cells with peripheral blood mononuclear cells (PBMCs). In an endothelial model grown on a permeable microfluidic bioscaffold under flow conditions, both human coronavirus (HCoV)-NL63 and SARS-CoV-2 presence diminished endothelial barrier function by disrupting VE-cadherin junctions and elevating the level of pro-inflammatory cytokines such as interleukin (IL)-6, IL-8, and angiopoietin-2. Inflammatory cytokine markers were markedly more elevated upon SARS-CoV-2 infection compared to HCoV-NL63 infection. Introduction of PBMCs with monocytes into the vasculature-on-a-chip upon SARS-CoV-2 infection further exacerbated cytokine-induced endothelial dysfunction, demonstrating the compounding effects of inter-cellular crosstalk between endothelial cells and monocytes in facilitating the hyperinflammatory state. Considering the harmful effects of SARS-CoV-2 on endothelial cells, even without active virus proliferation inside the cells, a potential therapeutic approach is critical. We identified angiopoietin-1 derived peptide, QHREDGS, as a potential therapeutic capable of profoundly attenuating the inflammatory state of the cells consistent with the levels in non-infected controls, thereby improving the barrier function and endothelial cell survival against SARS-CoV-2 infection in the presence of PBMC.


Subject(s)
Angiopoietin-1 , COVID-19 , Endothelium, Vascular , Inflammation , SARS-CoV-2 , COVID-19/drug therapy , COVID-19/virology , Endothelial Cells/immunology , Endothelial Cells/virology , Endothelium, Vascular/immunology , Endothelium, Vascular/virology , Humans , Immunity, Innate , Inflammation/drug therapy , Inflammation/virology , Lab-On-A-Chip Devices , Leukocytes, Mononuclear
2.
Proc Natl Acad Sci U S A ; 119(6)2022 02 08.
Article in English | MEDLINE | ID: covidwho-1655773

ABSTRACT

SARS-CoV-2 entry into host cells is a crucial step for virus tropism, transmission, and pathogenesis. Angiotensin-converting enzyme 2 (ACE2) has been identified as the primary entry receptor for SARS-CoV-2; however, the possible involvement of other cellular components in the viral entry has not yet been fully elucidated. Here we describe the identification of vimentin (VIM), an intermediate filament protein widely expressed in cells of mesenchymal origin, as an important attachment factor for SARS-CoV-2 on human endothelial cells. Using liquid chromatography-tandem mass spectrometry, we identified VIM as a protein that binds to the SARS-CoV-2 spike (S) protein. We showed that the S-protein receptor binding domain (RBD) is sufficient for S-protein interaction with VIM. Further analysis revealed that extracellular VIM binds to SARS-CoV-2 S-protein and facilitates SARS-CoV-2 infection, as determined by entry assays performed with pseudotyped viruses expressing S and with infectious SARS-CoV-2. Coexpression of VIM with ACE2 increased SARS-CoV-2 entry in HEK-293 cells, and shRNA-mediated knockdown of VIM significantly reduced SARS-CoV-2 infection of human endothelial cells. Moreover, incubation of A549 cells expressing ACE2 with purified VIM increased pseudotyped SARS-CoV-2-S entry. CR3022 antibody, which recognizes a distinct epitope on SARS-CoV-2-S-RBD without interfering with the binding of the spike with ACE2, inhibited the binding of VIM with CoV-2 S-RBD, and neutralized viral entry in human endothelial cells, suggesting a key role for VIM in SARS-CoV-2 infection of endothelial cells. This work provides insight into the pathogenesis of COVID-19 linked to the vascular system, with implications for the development of therapeutics and vaccines.


Subject(s)
Endothelial Cells/virology , Extracellular Space/metabolism , SARS-CoV-2/physiology , Spike Glycoprotein, Coronavirus/metabolism , Vimentin/metabolism , Virus Internalization , A549 Cells , Angiotensin-Converting Enzyme 2/metabolism , Coculture Techniques , Endothelium, Vascular/cytology , Endothelium, Vascular/metabolism , Endothelium, Vascular/virology , HEK293 Cells , Humans , Protein Binding
3.
Pharmacol Res Perspect ; 10(1): e00911, 2022 02.
Article in English | MEDLINE | ID: covidwho-1625316

ABSTRACT

Infection of humans with SARS-CoV-2 virus causes a disease known colloquially as "COVID-19" with symptoms ranging from asymptomatic to severe pneumonia. Initial pathology is due to the virus binding to the ACE-2 protein on endothelial cells lining blood vessels and entering these cells in order to replicate. Viral replication causes oxidative stress due to elevated levels of reactive oxygen species. Many (~60%) of the infected people appear to have eliminated the virus from their body after 28 days and resume normal activity. However, a significant proportion (~40%) experience a variety of symptoms (loss of smell and/or taste, fatigue, cough, aching pain, "brain fog," insomnia, shortness of breath, and tachycardia) after 12 weeks and are diagnosed with a syndrome named "LONG COVID." Longitudinal clinical studies in a group of subjects who were infected with SARS-CoV-2 have been compared to a non-infected matched group of subjects. A cohort of infected subjects can be identified by a battery of cytokine markers to have persistent, low level grade of inflammation and often self-report two or more troubling symptoms. There is no drug that will relieve their symptoms effectively. It is hypothesized that drugs that activate the intracellular transcription factor, nuclear factor erythroid-derived 2-like 2 (NRF2) may increase the expression of enzymes to synthesize the intracellular antioxidant, glutathione that will quench free radicals causing oxidative stress. The hormone melatonin has been identified as an activator of NRF2 and a relatively safe chemical for most people to ingest chronically. Thus, it is an option for consideration of re-purposing studies in "LONG COVID" subjects experiencing insomnia, depression, fatigue, and "brain fog" but not tachycardia. Appropriately designed clinical trials are required to evaluate melatonin.


Subject(s)
Antiviral Agents/therapeutic use , COVID-19/complications , Biomarkers/metabolism , COVID-19/drug therapy , COVID-19/physiopathology , COVID-19/virology , Endothelium, Vascular/virology , Humans , SARS-CoV-2/isolation & purification , SARS-CoV-2/physiology , Virus Replication
4.
Clin Hemorheol Microcirc ; 75(1): 7-11, 2020.
Article in English | MEDLINE | ID: covidwho-1581406

ABSTRACT

There is growing evidence that COVID-19 not only affects the lungs but beyond that the endothelial system. Recent studies showed that this can lead to microcirculatory impairments and in consequence to functional disorders of all inner organs. The combination of endothelial dysfunction with a generalized inflammatory state and complement elements may together contribute to the overall pro-coagulative state described in COVID-19 patients leading to venular as well as to arteriolar occlusions.


Subject(s)
Betacoronavirus/pathogenicity , Coronavirus Infections/pathology , Endothelium, Vascular/virology , Pneumonia, Viral/pathology , COVID-19 , Coronavirus Infections/virology , Endothelium, Vascular/pathology , Humans , Pandemics , Pneumonia, Viral/virology , SARS-CoV-2
5.
Signal Transduct Target Ther ; 6(1): 418, 2021 12 10.
Article in English | MEDLINE | ID: covidwho-1565706

ABSTRACT

The systemic processes involved in the manifestation of life-threatening COVID-19 and in disease recovery are still incompletely understood, despite investigations focusing on the dysregulation of immune responses after SARS-CoV-2 infection. To define hallmarks of severe COVID-19 in acute disease (n = 58) and in disease recovery in convalescent patients (n = 28) from Hannover Medical School, we used flow cytometry and proteomics data with unsupervised clustering analyses. In our observational study, we combined analyses of immune cells and cytokine/chemokine networks with endothelial activation and injury. ICU patients displayed an altered immune signature with prolonged lymphopenia but the expansion of granulocytes and plasmablasts along with activated and terminally differentiated T and NK cells and high levels of SARS-CoV-2-specific antibodies. The core signature of seven plasma proteins revealed a highly inflammatory microenvironment in addition to endothelial injury in severe COVID-19. Changes within this signature were associated with either disease progression or recovery. In summary, our data suggest that besides a strong inflammatory response, severe COVID-19 is driven by endothelial activation and barrier disruption, whereby recovery depends on the regeneration of the endothelial integrity.


Subject(s)
Antibodies, Viral/blood , Blood Proteins/metabolism , COVID-19/diagnosis , Cytokine Release Syndrome/diagnosis , Endothelium, Vascular/virology , Lymphopenia/diagnosis , SARS-CoV-2/pathogenicity , Biomarkers/blood , C-Reactive Protein/metabolism , COVID-19/immunology , COVID-19/mortality , COVID-19/virology , Chemokine CXCL10/blood , Chemokine CXCL9/blood , Cluster Analysis , Convalescence , Cytokine Release Syndrome/immunology , Cytokine Release Syndrome/mortality , Cytokine Release Syndrome/virology , Disease Progression , Endothelium, Vascular/immunology , Granulocytes/immunology , Granulocytes/virology , Hematopoietic Cell Growth Factors/blood , Hepatocyte Growth Factor/blood , Humans , Intensive Care Units , Interleukin-12 Subunit p40/blood , Interleukin-6/blood , Interleukin-8/blood , Killer Cells, Natural/immunology , Killer Cells, Natural/virology , Lectins, C-Type/blood , Lymphopenia/immunology , Lymphopenia/mortality , Lymphopenia/virology , Plasma Cells/immunology , Plasma Cells/virology , Survival Analysis , T-Lymphocytes/immunology , T-Lymphocytes/virology
6.
Hepatol Commun ; 6(2): 255-269, 2022 02.
Article in English | MEDLINE | ID: covidwho-1525435

ABSTRACT

Liver injury, characterized predominantly by elevated aspartate aminotransferase and alanine aminotransferase, is a common feature of coronavirus disease 2019 (COVID-19) symptoms caused by severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2). Additionally, SARS-CoV-2 infection is associated with acute-on-chronic liver failure in patients with cirrhosis and has a notably elevated mortality in patients with alcohol-related liver disease compared to other etiologies. Direct viral infection of the liver with SARS-CoV-2 remains controversial, and alternative pathophysiologic explanations for its hepatic effects are an area of active investigation. In this review, we discuss the effects of SARS-CoV-2 and the inflammatory environment it creates on endothelial cells and platelets more generally and then with a hepatic focus. In doing this, we present vascular inflammation and thrombosis as a potential mechanism of liver injury and liver-related complications in COVID-19.


Subject(s)
Blood Platelet Disorders/virology , COVID-19/physiopathology , Endothelium, Vascular/virology , Inflammation/virology , Liver Diseases/virology , Thrombosis/virology , Blood Platelet Disorders/immunology , Blood Platelet Disorders/physiopathology , COVID-19/immunology , Endothelium, Vascular/immunology , Endothelium, Vascular/physiopathology , Humans , Inflammation/immunology , Inflammation/physiopathology , Liver Diseases/immunology , Liver Diseases/physiopathology , Thrombosis/immunology , Thrombosis/physiopathology
7.
Clin Appl Thromb Hemost ; 27: 10760296211042940, 2021.
Article in English | MEDLINE | ID: covidwho-1484251

ABSTRACT

The world is in a hard battle against COVID-19. Endothelial cells are among the most critical targets of SARS-CoV-2. Dysfunction of endothelium leads to vascular injury following by coagulopathies and thrombotic conditions in the vital organs increasing the risk of life-threatening events. Growing evidences revealed that endothelial dysfunction and consequent thrombotic conditions are associated with the severity of outcomes. It is not yet fully clear that these devastating sequels originate directly from the virus or a side effect of virus-induced cytokine storm. Due to endothelial dysfunction, plasma levels of some biomarkers are changed and relevant clinical manifestations appear as well. Stabilization of endothelial integrity and supporting its function are among the promising therapeutic strategies. Other than respiratory, COVID-19 could be called a systemic vascular disease and this aspect should be scrutinized in more detail in order to reduce related mortality. In the present investigation, the effects of COVID-19 on endothelial function and thrombosis formation are discussed. In this regard, critical players, laboratory findings, clinical manifestation, and suggestive therapies are presented.


Subject(s)
Blood Coagulation , COVID-19/virology , Endothelial Cells/virology , Endothelium, Vascular/virology , SARS-CoV-2/pathogenicity , Thrombosis/virology , Animals , COVID-19/blood , COVID-19/pathology , COVID-19/physiopathology , Endothelial Cells/metabolism , Endothelial Cells/pathology , Endothelium, Vascular/metabolism , Endothelium, Vascular/physiopathology , Host-Pathogen Interactions , Humans , Signal Transduction , Thrombosis/blood , Thrombosis/pathology , Thrombosis/physiopathology
8.
Invest Ophthalmol Vis Sci ; 62(7): 6, 2021 06 01.
Article in English | MEDLINE | ID: covidwho-1388618

ABSTRACT

Purpose: To investigate the expression of angiotensin-converting enzyme 2 (ACE2), the receptor for SARS-CoV-2 in human retina. Methods: Human post-mortem eyes from 13 non-diabetic control cases and 11 diabetic retinopathy cases were analyzed for the expression of ACE2. To compare the vascular ACE2 expression between different organs that involve in diabetes, the expression of ACE2 was investigated in renal specimens from nondiabetic and diabetic nephropathy patients. Expression of TMPRSS2, a cell-surface protease that facilitates SARS-CoV-2 entry, was also investigated in human nondiabetic retinas. Primary human retinal endothelial cells (HRECs) and primary human retinal pericytes (HRPCs) were further used to confirm the vascular ACE2 expression in human retina. Results: We found that ACE2 was expressed in multiple nonvascular neuroretinal cells, including the retinal ganglion cell layer, inner plexiform layer, inner nuclear layer, and photoreceptor outer segments in both nondiabetic and diabetic retinopathy specimens. Strikingly, we observed significantly more ACE2 positive vessels in the diabetic retinopathy specimens. By contrast, in another end-stage organ affected by diabetes, the kidney, ACE2 in nondiabetic and diabetic nephropathy showed apical expression of ACE2 tubular epithelial cells, but no endothelial expression in glomerular or peritubular capillaries. Western blot analysis of protein lysates from HRECs and HRPCs confirmed expression of ACE2. TMPRSS2 expression was present in multiple retinal neuronal cells, vascular and perivascular cells, and Müller glia. Conclusions: Together, these results indicate that retina expresses ACE2 and TMPRSS2. Moreover, there are increased vascular ACE2 expression in diabetic retinopathy retinas.


Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , Diabetic Retinopathy/enzymology , Receptors, Virus/metabolism , Retina/enzymology , SARS-CoV-2/physiology , Adult , Aged , Aged, 80 and over , Binding Sites , Blotting, Western , Cells, Cultured , Diabetic Nephropathies/enzymology , Diabetic Nephropathies/pathology , Diabetic Nephropathies/virology , Diabetic Retinopathy/pathology , Diabetic Retinopathy/virology , Endothelium, Vascular/enzymology , Endothelium, Vascular/virology , Female , Fluorescent Antibody Technique, Indirect , Humans , Immunohistochemistry , Male , Middle Aged , Pericytes/enzymology , Pericytes/virology , Retinal Vessels/enzymology , Retinal Vessels/pathology , Retinal Vessels/virology , Serine Endopeptidases/metabolism
10.
Ann Vasc Surg ; 72: 209-215, 2021 Apr.
Article in English | MEDLINE | ID: covidwho-1385038

ABSTRACT

BACKGROUND: Both arterial and venous thrombotic events of the extremities occur in coronavirus disease 2019 (COVID-19) infection, but the etiology of these events remains unclear. This study sought to evaluate pathology specimens of COVID-19-positive patients postamputation, who were found to have Rutherford 3 acute limb ischemia requiring amputation. METHODS: A retrospective review was performed of all vascular surgery emergency room and inpatient consultations in patients who presented to the Mount Sinai Health System from March 26, 2020, to May 10, 2020. Pathology specimens were examined using hematoxylin and eosin stain. The specimens were assessed for the following: inflammatory cells associated with endothelium/apoptotic bodies, mononuclear cells, small vessel congestion, and lymphocytic endotheliitis. Of the specimens evaluated, 2 patients with a known history of peripheral vascular disease were excluded. RESULTS: Inflammatory cells associated with endothelium/apoptotic bodies were seen in all 4 patients and in 4 of 5 specimens. Mononuclear cells were found in 2 of 4 patients. Small vessel congestion was seen in all patients. Lymphocytic endotheliitis was seen in 1 of 4 patients. CONCLUSIONS: This study shows endotheliitis in amputation specimens of four patients with COVID-19 disease and Rutherford Class 3 acute limb ischemia. The findings in these patients is more likely an infectious angiitis because of COVID-19.


Subject(s)
Amputation , COVID-19/complications , Endothelium, Vascular/virology , Lower Extremity/blood supply , Lower Extremity/surgery , Thrombosis/surgery , Thrombosis/virology , Acute Disease , Aged , Aged, 80 and over , Female , Humans , Male , Middle Aged , Pandemics , Retrospective Studies , SARS-CoV-2
11.
Scand J Immunol ; 94(5): e13097, 2021 Nov.
Article in English | MEDLINE | ID: covidwho-1388398

ABSTRACT

COVID-19 is a global pandemic with a daily increasing number of affected individuals. Thrombosis is a severe complication of COVID-19 that leads to a worse clinical course with higher rates of mortality. Multiple lines of evidence suggest that hyperinflammation plays a crucial role in disease progression. This review compiles clinical data of COVID-19 patients who developed thrombotic complications to investigate the possible role of hyperinflammation in inducing hypercoagulation. A systematic literature search was performed using PubMed, Embase, Medline and Scopus to identify relevant clinical studies that investigated thrombotic manifestations and reported inflammatory and coagulation biomarkers in COVID-19 patients. Only 54 studies met our inclusion criteria, the majority of which demonstrated significantly elevated inflammatory markers. In the cohort studies with control, D-dimer was significantly higher in COVID-19 patients with thrombosis as compared to the control. Pulmonary embolism, deep vein thrombosis and strokes were frequently reported which could be attributed to the hyperinflammatory response associated with COVID-19 and/or to the direct viral activation of platelets and endothelial cells, two mechanisms that are discussed in this review. It is recommended that all admitted COVID-19 patients should be assessed for hypercoagulation. Furthermore, several studies have suggested that anticoagulation may be beneficial, especially in hospitalized non-ICU patients. Although vaccines against SARS-CoV-2 have been approved and distributed in several countries, research should continue in the field of prevention and treatment of COVID-19 and its severe complications including thrombosis due to the emergence of new variants against which the efficacy of the vaccines is not yet clear.


Subject(s)
Arteries/pathology , Blood Platelets/immunology , COVID-19/immunology , Endothelium, Vascular/immunology , Inflammation/immunology , SARS-CoV-2/physiology , Venous Thrombosis/immunology , Animals , Anticoagulants/therapeutic use , Blood Platelets/virology , COVID-19/complications , Endothelium, Vascular/virology , Humans , Inflammation/complications , Phenotype , Thrombosis , Venous Thrombosis/etiology , Venous Thrombosis/prevention & control
12.
Oxid Med Cell Longev ; 2021: 8671713, 2021.
Article in English | MEDLINE | ID: covidwho-1378091

ABSTRACT

The outbreak of the COVID-19 pandemic represents an ongoing healthcare emergency responsible for more than 3.4 million deaths worldwide. COVID-19 is the disease caused by SARS-CoV-2, a virus that targets not only the lungs but also the cardiovascular system. COVID-19 can manifest with a wide range of clinical manifestations, from mild symptoms to severe forms of the disease, characterized by respiratory failure due to severe alveolar damage. Several studies investigated the underlying mechanisms of the severe lung damage associated with SARS-CoV-2 infection and revealed that the respiratory failure associated with COVID-19 is the consequence not only of acute respiratory distress syndrome but also of macro- and microvascular involvement. New observations show that COVID-19 is an endothelial disease, and the consequent endotheliopathy is responsible for inflammation, cytokine storm, oxidative stress, and coagulopathy. In this review, we show the central role of endothelial dysfunction, inflammation, and oxidative stress in the COVID-19 pathogenesis and present the therapeutic targets deriving from this endotheliopathy.


Subject(s)
COVID-19/complications , Cytokine Release Syndrome/pathology , Endothelium, Vascular/pathology , Inflammation/pathology , Oxidative Stress , SARS-CoV-2/isolation & purification , Vascular Diseases/pathology , COVID-19/virology , Cytokine Release Syndrome/etiology , Cytokine Release Syndrome/therapy , Endothelium, Vascular/virology , Humans , Inflammation/etiology , Inflammation/therapy , Vascular Diseases/etiology , Vascular Diseases/therapy
13.
Am J Physiol Lung Cell Mol Physiol ; 321(2): L358-L376, 2021 08 01.
Article in English | MEDLINE | ID: covidwho-1280497

ABSTRACT

Capillary endothelial cells possess a specialized metabolism necessary to adapt to the unique alveolar-capillary environment. Here, we highlight how endothelial metabolism preserves the integrity of the pulmonary circulation by controlling vascular permeability, defending against oxidative stress, facilitating rapid migration and angiogenesis in response to injury, and regulating the epigenetic landscape of endothelial cells. Recent reports on single-cell RNA-sequencing reveal subpopulations of pulmonary capillary endothelial cells with distinctive reparative capacities, which potentially offer new insight into their metabolic signature. Lastly, we discuss broad implications of pulmonary vascular metabolism on acute respiratory distress syndrome, touching on emerging findings of endotheliitis in coronavirus disease 2019 (COVID-19) lungs.


Subject(s)
COVID-19/complications , Endothelium, Vascular/metabolism , Neovascularization, Pathologic/pathology , Pulmonary Circulation , Respiratory Distress Syndrome/epidemiology , SARS-CoV-2/isolation & purification , COVID-19/transmission , COVID-19/virology , Endothelium, Vascular/pathology , Endothelium, Vascular/virology , Humans , Neovascularization, Pathologic/metabolism , Neovascularization, Pathologic/virology , Respiratory Distress Syndrome/metabolism , Respiratory Distress Syndrome/pathology , Respiratory Distress Syndrome/virology
14.
PLoS One ; 16(6): e0253347, 2021.
Article in English | MEDLINE | ID: covidwho-1280628

ABSTRACT

The unprecedented global COVID-19 pandemic has prompted a desperate international effort to accelerate the development of anti-viral candidates. For unknown reasons, COVID-19 infections are associated with adverse cardiovascular complications, implicating that vascular endothelial cells are essential in viral propagation. The etiological pathogen, SARS-CoV-2, has a higher reproductive number and infection rate than its predecessors, indicating it possesses novel characteristics that infers enhanced transmissibility. A unique K403R spike protein substitution encodes an Arg-Gly-Asp (RGD) motif, introducing a potential role for RGD-binding host integrins. Integrin αVß3 is widely expressed across the host, particularly in the endothelium, which acts as the final barrier before microbial entry into the bloodstream. This mutagenesis creates an additional binding site, which may be sufficient to increase SARS-CoV-2 pathogenicity. Here, we investigate how SARS-CoV-2 passes from the epithelium to endothelium, the effects of αVß3 antagonist, Cilengitide, on viral adhesion, vasculature permeability and leakage, and also report on a simulated interaction between the viral and host protein in-silico.


Subject(s)
Endothelium, Vascular/virology , Integrin alphaVbeta3/metabolism , SARS-CoV-2/pathogenicity , Snake Venoms/pharmacology , Antigens, CD/metabolism , Binding Sites , COVID-19/metabolism , COVID-19/physiopathology , Caco-2 Cells , Cadherins/metabolism , Computer Simulation , Endothelium, Vascular/cytology , Endothelium, Vascular/physiopathology , Host-Pathogen Interactions/drug effects , Humans , Integrin alphaVbeta3/chemistry , Models, Molecular , Mutation , Permeability , SARS-CoV-2/drug effects , SARS-CoV-2/genetics , SARS-CoV-2/metabolism , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/metabolism , Virus Internalization
15.
Mol Neurobiol ; 58(9): 4575-4587, 2021 Sep.
Article in English | MEDLINE | ID: covidwho-1263176

ABSTRACT

Severe acute respiratory syndrome coronavirus (SARS-CoV)-2 or COVID-19 has been declared as a pandemic disease by the World Health Organization (WHO). Globally, this disease affected 159 million of the population and reported ~ 3.3 million deaths to the current date (May 2021). There is no definitive treatment strategy that has been identified, although this disease has prevailed in its current form for the past 18 months. The main challenges in the (SARS-CoV)-2 infections are in identifying the heterogeneity in viral strains and the plausible mechanisms of viral infection to human tissues. In parallel to the investigations into the patho-mechanism of SARS-CoV-2 infection, understanding the fundamental processes underlying the clinical manifestations of COVID-19 is very crucial for designing effective therapies. Since neurological symptoms are very apparent in COVID-19 infected patients, here, we tried to emphasize the involvement of redox imbalance and subsequent mitochondrial dysfunction in the progression of the COVID-19 infection. It has been articulated that mitochondrial dysfunction is very apparent and also interlinked to neurological symptoms in COVID-19 infection. Overall, this article provides an in-depth overview of redox imbalance and mitochondrial dysfunction involvement in aggravating COVID-19 infection and its probable contribution to the neurological manifestation of the disease.


Subject(s)
COVID-19/complications , Mitochondria/physiology , SARS-CoV-2/pathogenicity , Animals , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , COVID-19/metabolism , Central Nervous System/virology , Drug Repositioning , Endothelium, Vascular/physiopathology , Endothelium, Vascular/virology , Humans , Mice , Mitochondria/drug effects , Mitochondria/pathology , Models, Biological , Olfactory Nerve/virology , Organ Specificity , Oxidation-Reduction , Oxidative Stress/drug effects , Pandemics , SARS-CoV-2/physiology , Viral Proteins/physiology , Viral Tropism , Viremia/complications , Virulence , Virus Internalization
16.
Mol Neurobiol ; 58(9): 4487-4494, 2021 Sep.
Article in English | MEDLINE | ID: covidwho-1242821

ABSTRACT

Headache is the most common neurological symptom in COVID-19, reported in 6.5 to 34% of patients. Few studies have analyzed its characteristics, and some of them included cases without laboratory confirmation or reported only critical patients. We aimed to analyze the clinical characteristics of COVID-19 associated headache in laboratory-confirmed cases. We conducted a retrospective evaluation of patients with COVID-19 and neurological symptoms. Patients who reported headache answered an interview about its clinical characteristics. Twenty-four patients with COVID-19 associated headache completed the interview. Mean age of patients was 53.8 (standard deviation-17.44), and 14 out of 24 (58.3%) were male. The majority (75%) had no previous history of headache. Fever was documented in 19 out of the 24 patients (79.1%). Headache was predominantly bifrontal or holocranial, in pressure, during hours, worsening with cough or physical activity. COVID-19 headache tends to appear in the first days of symptoms, be either frontal or holocranial and last for days. The quality of pain in pressure and the worsening with cough or physical activity were reported in most cases. We have not found any characteristic that could differentiate COVID-19 associated headache from other causes of headache, possibly because of its multifactorial mechanism.


Subject(s)
COVID-19/complications , Headache/etiology , SARS-CoV-2 , Adolescent , Adult , Antihypertensive Agents/therapeutic use , COVID-19/diagnosis , COVID-19/epidemiology , COVID-19 Testing , Comorbidity , Cytokines/physiology , Endothelium, Vascular/physiopathology , Endothelium, Vascular/virology , Female , Fever/etiology , Headache/physiopathology , Humans , Inflammation , Male , Models, Biological , Neoplasms/epidemiology , Retrospective Studies , Symptom Assessment , Trigeminal Nerve/virology , Young Adult
17.
Int J Mol Sci ; 22(10)2021 May 12.
Article in English | MEDLINE | ID: covidwho-1227032

ABSTRACT

The outbreak of coronavirus disease 2019 (COVID-19) caused by the betacoronavirus SARS-CoV-2 is now a worldwide challenge for healthcare systems. Although the leading cause of mortality in patients with COVID-19 is hypoxic respiratory failure due to viral pneumonia and acute respiratory distress syndrome, accumulating evidence has shown that the risk of thromboembolism is substantially high in patients with severe COVID-19 and that a thromboembolic event is another major complication contributing to the high morbidity and mortality in patients with COVID-19. Endothelial dysfunction is emerging as one of the main contributors to the pathogenesis of thromboembolic events in COVID-19. Endothelial dysfunction is usually referred to as reduced nitric oxide bioavailability. However, failures of the endothelium to control coagulation, inflammation, or permeability are also instances of endothelial dysfunction. Recent studies have indicated the possibility that SARS-CoV-2 can directly infect endothelial cells via the angiotensin-converting enzyme 2 pathway and that endothelial dysfunction caused by direct virus infection of endothelial cells may contribute to thrombotic complications and severe disease outcomes in patients with COVID-19. In this review, we summarize the current understanding of relationships between SARS-CoV-2 infection, endothelial dysfunction, and pulmonary and extrapulmonary complications in patients with COVID-19.


Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , COVID-19/mortality , COVID-19/physiopathology , Cytokines/metabolism , Endothelial Cells/virology , Endothelium, Vascular/virology , Thromboembolism/virology , COVID-19/complications , COVID-19/virology , Endothelial Cells/pathology , Endothelium, Vascular/pathology , Humans , Inflammation/metabolism , Inflammation/pathology , Lung/pathology , Lung/virology , Pneumonia, Viral/complications , Pneumonia, Viral/pathology , Respiratory Distress Syndrome/complications , Respiratory Distress Syndrome/virology , SARS-CoV-2/pathogenicity , Thromboembolism/complications
19.
J Infect Dis ; 223(5): 752-764, 2021 03 03.
Article in English | MEDLINE | ID: covidwho-1117027

ABSTRACT

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic continues to produce substantial morbidity and mortality. To understand the reasons for the wide-spectrum complications and severe outcomes of COVID-19, we aimed to identify cellular targets of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) tropism and replication in various tissues. METHODS: We evaluated RNA extracted from formalin-fixed, paraffin-embedded autopsy tissues from 64 case patients (age range, 1 month to 84 years; 21 COVID-19 confirmed, 43 suspected COVID-19) by SARS-CoV-2 reverse-transcription polymerase chain reaction (RT-PCR). For cellular localization of SARS-CoV-2 RNA and viral characterization, we performed in situ hybridization (ISH), subgenomic RNA RT-PCR, and whole-genome sequencing. RESULTS: SARS-CoV-2 was identified by RT-PCR in 32 case patients (21 COVID-19 confirmed, 11 suspected). ISH was positive in 20 and subgenomic RNA RT-PCR was positive in 17 of 32 RT-PCR-positive case patients. SARS-CoV-2 RNA was localized by ISH in hyaline membranes, pneumocytes, and macrophages of lungs; epithelial cells of airways; and endothelial cells and vessel walls of brain stem, leptomeninges, lung, heart, liver, kidney, and pancreas. The D614G variant was detected in 9 RT-PCR-positive case patients. CONCLUSIONS: We identified cellular targets of SARS-CoV-2 tropism and replication in the lungs and airways and demonstrated its direct infection in vascular endothelium. This work provides important insights into COVID-19 pathogenesis and mechanisms of severe outcomes.


Subject(s)
COVID-19/virology , Endothelium, Vascular/virology , Respiratory System/virology , SARS-CoV-2/physiology , Virus Replication , Adolescent , Adult , Aged , Aged, 80 and over , Autopsy , COVID-19/complications , COVID-19 Nucleic Acid Testing , Child , Child, Preschool , Female , Humans , In Situ Hybridization , Infant , Lung/virology , Male , Middle Aged , RNA, Viral/isolation & purification , Real-Time Polymerase Chain Reaction , SARS-CoV-2/genetics , SARS-CoV-2/isolation & purification , Viral Tropism , Whole Genome Sequencing , Young Adult
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