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1.
Viral Immunol ; 34(3): 165-173, 2021 04.
Article in English | MEDLINE | ID: covidwho-1569564

ABSTRACT

The current pandemic is caused by the coronavirus disease 2019 (COVID-19), which is, in turn, induced by a novel coronavirus (SARS-CoV-2) that triggers an acute respiratory disease. In recent years, the emergence of SARS-CoV-2 is the third highly pathogenic event and large-scale epidemic affecting the human population. It follows the severe acute respiratory syndrome coronavirus (SARS-CoV) in 2003 and the Middle East respiratory syndrome coronavirus (MERS-CoV) in 2012. This novel SARS-CoV-2 employs the angiotensin-converting enzyme 2 (ACE2) receptor, like SARS-CoV, and spreads principally in the respiratory tract. The viral spike (S) protein of coronaviruses facilities the attachment to the cellular receptor, entrance, and membrane fusion. The S protein is a glycoprotein and is critical to elicit an immune response. Glycosylation is a biologically significant post-translational modification in virus surface proteins. These glycans play important roles in the viral life cycle, structure, immune evasion, and cell infection. However, it is necessary to search for new information about viral behavior and immunological host's response after SARS-CoV-2 infection. The present review discusses the implications of the CoV-2 S protein glycosylation in the SARS-CoV-2/ACE2 interaction and the immunological response. Elucidation of the glycan repertoire on the spike protein can propel research for the development of an appropriate vaccine.


Subject(s)
Angiotensin-Converting Enzyme 2/physiology , COVID-19/immunology , SARS-CoV-2/physiology , Spike Glycoprotein, Coronavirus/physiology , Glycosylation , Humans , SARS-CoV-2/chemistry , SARS-CoV-2/genetics
2.
PLoS Comput Biol ; 17(11): e1009560, 2021 11.
Article in English | MEDLINE | ID: covidwho-1523396

ABSTRACT

Severe acute respiratory coronavirus 2 (SARS-CoV-2), the causative agent of COVID-19, is of zoonotic origin. Evolutionary analyses assessing whether coronaviruses similar to SARS-CoV-2 infected ancestral species of modern-day animal hosts could be useful in identifying additional reservoirs of potentially dangerous coronaviruses. We reasoned that if a clade of species has been repeatedly exposed to a virus, then their proteins relevant for viral entry may exhibit adaptations that affect host susceptibility or response. We perform comparative analyses across the mammalian phylogeny of angiotensin-converting enzyme 2 (ACE2), the cellular receptor for SARS-CoV-2, in order to uncover evidence for selection acting at its binding interface with the SARS-CoV-2 spike protein. We uncover that in rodents there is evidence for adaptive amino acid substitutions at positions comprising the ACE2-spike interaction interface, whereas the variation within ACE2 proteins in primates and some other mammalian clades is not consistent with evolutionary adaptations. We also analyze aminopeptidase N (APN), the receptor for the human coronavirus 229E, a virus that causes the common cold, and find evidence for adaptation in primates. Altogether, our results suggest that the rodent and primate lineages may have had ancient exposures to viruses similar to SARS-CoV-2 and HCoV-229E, respectively.


Subject(s)
COVID-19/genetics , COVID-19/virology , Coronavirus Infections/genetics , Coronavirus Infections/virology , SARS-CoV-2/genetics , Adaptation, Physiological/genetics , Amino Acid Substitution , Angiotensin-Converting Enzyme 2/genetics , Angiotensin-Converting Enzyme 2/physiology , Animals , CD13 Antigens/genetics , CD13 Antigens/physiology , Common Cold/genetics , Common Cold/virology , Computational Biology , Coronavirus 229E, Human/genetics , Coronavirus 229E, Human/physiology , Evolution, Molecular , Genomics , Host Microbial Interactions/genetics , Host Microbial Interactions/physiology , Host Specificity/genetics , Host Specificity/physiology , Humans , Mammals/genetics , Mammals/virology , Phylogeny , Protein Interaction Domains and Motifs/genetics , Receptors, Virus/genetics , Receptors, Virus/physiology , SARS-CoV-2/physiology , Selection, Genetic , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/physiology , Virus Internalization
3.
Hamostaseologie ; 41(5): 387-396, 2021 Oct.
Article in English | MEDLINE | ID: covidwho-1483190

ABSTRACT

Hypercoagulability and vascular injury, which characterize morbidity in COVID-19 disease, are frequently observed in the skin. Several pathomechanisms, such as inflammation caused by angiotensin-converting enzyme 2-mediated uptake into endothelial cells or SARS-CoV-2-initiated host immune responses, contribute to microthrombus formation and the appearance of vascular skin lesions. Besides pathophysiologic mechanisms observed in the skin, this review describes the clinical appearance of cutaneous vascular lesions and their association with COVID-19 disease, including acro-ischemia, reticular lesions, and cutaneous small vessel vasculitis. Clinicians need to be aware that skin manifestations may be the only symptom in SARS-CoV-2 infection, and that inflammatory and thrombotic SARS-CoV-2-driven processes observed in multiple organs and tissues appear identically in the skin as well.


Subject(s)
COVID-19/complications , SARS-CoV-2 , Skin/blood supply , Angiotensin-Converting Enzyme 2/physiology , Antibodies, Antiphospholipid/blood , Blood Coagulation Disorders/blood , Blood Coagulation Disorders/etiology , Blood Coagulation Disorders/pathology , COVID-19/pathology , COVID-19/physiopathology , Complement Activation , Cytokines/metabolism , Host Microbial Interactions/immunology , Host Microbial Interactions/physiology , Humans , Microvessels/immunology , Microvessels/pathology , Microvessels/physiopathology , Pandemics , SARS-CoV-2/pathogenicity , SARS-CoV-2/physiology , Skin/immunology , Vasculitis/etiology , Vasculitis/pathology , Vasculitis/physiopathology , Virus Internalization
4.
Trop Biomed ; 38(3): 360-365, 2021 Sep 01.
Article in English | MEDLINE | ID: covidwho-1404405

ABSTRACT

COVID-19, caused by the SARS-CoV-2 virus, can lead to massive inflammation in the gastrointestinal tract causing severe clinical symptoms. SARS-CoV-2 infects lungs after binding its spike proteins with alveolar angiotensin-converting enzyme 2 (ACE2), and it also triggers inflammation in the gastrointestinal tract. SARS-CoV-2 invades the gastrointestinal tract by interacting with Toll-like receptor-4 (TLR4) that induces the expression of ACE2. The influx of ACE2 facilitates cellular binding of more SARS-CoV-2 and causes massive gastrointestinal inflammation leading to diarrhea. Diarrhea prior to COVID-19 infection or COVID-19-induced diarrhea reportedly ends up in a poor prognosis for the patient. Flavonoids are part of traditional remedies for gastrointestinal disorders. Preclinical studies show that flavonoids can prevent infectious diarrhea. Recent studies show flavonoids can inhibit the multiplication of SARS-CoV-2. In combination with vitamin D, flavonoids possibly activate nuclear factor erythroid-derived-2-related factor 2 that downregulates ACE2 expression in cells. We suggest that flavonoids have the potential to prevent SARS-CoV-2 induced diarrhea.


Subject(s)
COVID-19/complications , Diarrhea/prevention & control , Flavonoids/therapeutic use , SARS-CoV-2 , Angiotensin-Converting Enzyme 2/physiology , Diarrhea/etiology , Humans
6.
Neuropharmacology ; 198: 108766, 2021 10 15.
Article in English | MEDLINE | ID: covidwho-1376075

ABSTRACT

The coronavirus disease 2019 (Covid-19) pandemic intensified the already catastrophic drug overdose and substance use disorder (SUD) epidemic, signaling a syndemic as social isolation, economic and mental health distress, and disrupted treatment services disproportionally impacted this vulnerable population. Along with these social and societal factors, biological factors triggered by intense stress intertwined with incumbent overactivity of the immune system and the resulting inflammatory outcomes may impact the functional status of the central nervous system (CNS). We review the literature concerning SARS-CoV2 infiltration and infection in the CNS and the prospects of synergy between stress, inflammation, and kynurenine pathway function during illness and recovery from Covid-19. Taken together, inflammation and neuroimmune signaling, a consequence of Covid-19 infection, may dysregulate critical pathways and underlie maladaptive changes in the CNS, to exacerbate the development of neuropsychiatric symptoms and in the vulnerability to develop SUD. This article is part of the special Issue on 'Vulnerabilities to Substance Abuse'.


Subject(s)
COVID-19/epidemiology , Drug Misuse/statistics & numerical data , SARS-CoV-2 , Substance-Related Disorders/epidemiology , Adaptation, Psychological , Angiotensin-Converting Enzyme 2/physiology , Animals , Axons/virology , COVID-19/immunology , COVID-19/physiopathology , COVID-19/psychology , Comorbidity , Disease Susceptibility , Endothelial Cells/virology , Humans , Immunity, Innate , Inflammation/etiology , Kynurenine/metabolism , Neurons/virology , Neurotransmitter Agents/metabolism , Olfactory Mucosa/virology , Pandemics , SARS-CoV-2/physiology , Social Isolation , Stress, Psychological , Substance-Related Disorders/etiology , Substance-Related Disorders/physiopathology , Tryptophan/metabolism , Viral Tropism
7.
FASEB J ; 35(9): e21798, 2021 09.
Article in English | MEDLINE | ID: covidwho-1334263

ABSTRACT

The coronavirus disease 2019 (COVID-19) pandemic threatens human species with mortality rate of roughly 2%. We can hardly predict the time of herd immunity against and end of COVID-19 with or without success of vaccine. One way to overcome the situation is to define what delineates disease severity and serves as a molecular target. The most successful analogy is found in BCR-ABL in chronic myeloid leukemia, which is the golden biomarker, and simultaneously, the most effective molecular target. We hypothesize that S100 calcium-binding protein A8 (S100A8) is one such molecule. The underlying evidence includes accumulating clinical information that S100A8 is upregulated in severe forms of COVID-19, pathological similarities of the affected lungs between COVID-19 and S100A8-induced acute respiratory distress syndrome (ARDS) model, homeostatic inflammation theory in which S100A8 is an endogenous ligand for endotoxin sensor Toll-like receptor 4/Myeloid differentiation protein-2 (TLR4/MD-2) and mediates hyper-inflammation even after elimination of endotoxin-producing extrinsic pathogens, analogous findings between COVID-19-associated ARDS and pre-metastatic lungs such as S100A8 upregulation, pulmonary recruitment of myeloid cells, increased vascular permeability, and activation coagulation cascade. A successful treatment in an animal COVID-19 model is given with a reagent capable of abrogating interaction between S100A8/S100A9 and TLR4. In this paper, we try to verify our hypothesis that S100A8 governs COVID-19-associated ARDS.


Subject(s)
COVID-19/complications , Calgranulin A/physiology , Cytokine Release Syndrome/etiology , Inflammation/etiology , Pandemics , Respiratory Distress Syndrome/etiology , SARS-CoV-2/genetics , Angiotensin-Converting Enzyme 2/genetics , Angiotensin-Converting Enzyme 2/physiology , Animals , Antiviral Agents/pharmacology , COVID-19/genetics , COVID-19/pathology , Calgranulin A/blood , Calgranulin A/genetics , Chemokine CXCL11/blood , Cytokine Release Syndrome/genetics , Cytokine Release Syndrome/pathology , Disaccharides/pharmacology , Disaccharides/therapeutic use , Disease Models, Animal , Drug Discovery , Epithelial Cells/metabolism , Epithelial Cells/virology , Humans , Inflammation/genetics , Inflammation/pathology , Lung/metabolism , Lung/pathology , Lung/virology , Lung Neoplasms/drug therapy , Lung Neoplasms/secondary , Lymphocyte Antigen 96/physiology , Macaca mulatta , Mice , Mice, Transgenic , Models, Biological , Mutation , Respiratory Distress Syndrome/genetics , Respiratory Distress Syndrome/metabolism , Species Specificity , Sugar Phosphates/pharmacology , Sugar Phosphates/therapeutic use , Toll-Like Receptor 4/physiology , Up-Regulation , Virus Internalization
8.
Clin J Am Soc Nephrol ; 16(7): 1061-1072, 2021 07.
Article in English | MEDLINE | ID: covidwho-1332080

ABSTRACT

BACKGROUND AND OBJECTIVES: There is concern about potential deleterious effects of angiotensin-converting enzyme inhibitors (ACEis) and angiotensin II receptor blockers (ARBs) in patients with coronavirus disease 2019 (COVID-19). Patients with kidney failure, who often use ACEis/ARBs, are at higher risk of more severe COVID-19. However, there are no data available on the association of ACEi/ARB use with COVID-19 severity in this population. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: From the European Renal Association COVID-19 database (ERACODA), we retrieved data on kidney transplant recipients and patients on dialysis who were affected by COVID-19, between February 1 and October 1, 2020, and had information on 28-day mortality. We used Cox proportional-hazards regression to calculate hazard ratios for the association between ACEi/ARB use and 28-day mortality risk. Additionally, we studied the association of discontinuation of these agents with 28-day mortality. RESULTS: We evaluated 1511 patients: 459 kidney transplant recipients and 1052 patients on dialysis. At diagnosis of COVID-19, 189 (41%) of the transplant recipients and 288 (27%) of the patients on dialysis were on ACEis/ARBs. A total of 88 (19%) transplant recipients and 244 (23%) patients on dialysis died within 28 days of initial presentation. In both groups of patients, there was no association between ACEi/ARB use and 28-day mortality in both crude and adjusted models (in transplant recipients, adjusted hazard ratio, 1.12; 95% confidence interval [95% CI], 0.69 to 1.83; in patients on dialysis, adjusted hazard ratio, 1.04; 95% CI, 0.73 to 1.47). Among transplant recipients, ACEi/ARB discontinuation was associated with a higher mortality risk after adjustment for demographics and comorbidities, but the association was no longer statistically significant after adjustment for severity of COVID-19 (adjusted hazard ratio, 1.36; 95% CI, 0.40 to 4.58). Among patients on dialysis, ACEi/ARB discontinuation was not associated with mortality in any model. We obtained similar results across subgroups when ACEis and ARBs were studied separately, and when other outcomes for severity of COVID-19 were studied, e.g., hospital admission, admission to the intensive care unit, or need for ventilator support. CONCLUSIONS: Among kidney transplant recipients and patients on dialysis with COVID-19, there was no significant association of ACEi/ARB use or discontinuation with mortality.


Subject(s)
Angiotensin Receptor Antagonists/adverse effects , Angiotensin-Converting Enzyme Inhibitors/adverse effects , COVID-19/mortality , Renal Insufficiency/complications , SARS-CoV-2 , Aged , Aged, 80 and over , Angiotensin-Converting Enzyme 2/physiology , Female , Hospitalization , Humans , Kidney Transplantation , Male , Middle Aged , Proportional Hazards Models
10.
J Clin Invest ; 131(14)2021 07 15.
Article in English | MEDLINE | ID: covidwho-1311200

ABSTRACT

The coronavirus disease 2019 (COVID-19) pandemic is among the most important public health crises of our generation. Despite the promise of prevention offered by effective vaccines, patients with severe COVID-19 will continue to populate hospitals and intensive care units for the foreseeable future. The most common clinical presentation of severe COVID-19 is hypoxemia and respiratory failure, typical of the acute respiratory distress syndrome (ARDS). Whether the clinical features and pathobiology of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pneumonia differ from those of pneumonia secondary to other pathogens is unclear. This uncertainty has created variability in the application of historically proven therapies for ARDS to patients with COVID-19. We review the available literature and find many similarities between patients with ARDS from pneumonia attributable to SARS-CoV-2 versus other respiratory pathogens. A notable exception is the long duration of illness among patients with COVID-19, which could result from its unique pathobiology. Available data support the use of care pathways and therapies proven effective for patients with ARDS, while pointing to unique features that might be therapeutically targeted for patients with severe SARS-CoV-2 pneumonia.


Subject(s)
COVID-19/etiology , Pneumonia, Viral/etiology , Respiratory Distress Syndrome/etiology , SARS-CoV-2 , Angiotensin-Converting Enzyme 2/physiology , Autopsy , COVID-19/epidemiology , COVID-19/pathology , Cytokines/biosynthesis , Humans , Lung/immunology , Lung/pathology , Lung/virology , Macrophages, Alveolar/immunology , Macrophages, Alveolar/virology , Models, Biological , Pandemics , Pneumonia, Viral/immunology , Pneumonia, Viral/pathology , Receptors, Virus/physiology , Respiratory Distress Syndrome/immunology , Respiratory Distress Syndrome/pathology , SARS-CoV-2/immunology , SARS-CoV-2/pathogenicity , SARS-CoV-2/physiology , Severity of Illness Index
11.
Emerg Microbes Infect ; 10(1): 1507-1514, 2021 Dec.
Article in English | MEDLINE | ID: covidwho-1310873

ABSTRACT

Severe respiratory disease coronavirus-2 (SARS-CoV-2) has been the most devastating disease COVID-19 in the century. One of the unsolved scientific questions of SARS-CoV-2 is the animal origin of this virus. Bats and pangolins are recognized as the most probable reservoir hosts that harbour highly similar SARS-CoV-2 related viruses (SARSr-CoV-2). This study identified a novel lineage of SARSr-CoVs, including RaTG15 and seven other viruses, from bats at the same location where we found RaTG13 in 2015. Although RaTG15 and the related viruses share 97.2% amino acid sequence identities with SARS-CoV-2 in the conserved ORF1b region, it only shows less than 77.6% nucleotide identity to all known SARSr-CoVs at the genome level, thus forming a distinct lineage in the Sarbecovirus phylogenetic tree. We found that the RaTG15 receptor-binding domain (RBD) can bind to ACE2 from Rhinolophus affinis, Malayan pangolin, and use it as an entry receptor, except for ACE2 from humans. However, it contains a short deletion and has different key residues responsible for ACE2 binding. In addition, we showed that none of the known viruses in bat SARSr-CoV-2 lineage discovered uses human ACE2 as efficiently as the pangolin-derived SARSr-CoV-2 or some viruses in the SARSr-CoV-1 lineage. Therefore, further systematic and longitudinal studies in bats are needed to prevent future spillover events caused by SARSr-CoVs or to understand the origin of SARS-CoV-2 better.


Subject(s)
Angiotensin-Converting Enzyme 2/physiology , Cell Lineage , Chiroptera/virology , SARS Virus/isolation & purification , SARS-CoV-2/classification , Animals , Host Specificity , Phylogeny , SARS Virus/classification
12.
PLoS Pathog ; 17(7): e1009706, 2021 07.
Article in English | MEDLINE | ID: covidwho-1305581

ABSTRACT

Many viruses utilize the host endo-lysosomal network for infection. Tracing the endocytic itinerary of SARS-CoV-2 can provide insights into viral trafficking and aid in designing new therapeutic strategies. Here, we demonstrate that the receptor binding domain (RBD) of SARS-CoV-2 spike protein is internalized via the pH-dependent CLIC/GEEC (CG) endocytic pathway in human gastric-adenocarcinoma (AGS) cells expressing undetectable levels of ACE2. Ectopic expression of ACE2 (AGS-ACE2) results in RBD traffic via both CG and clathrin-mediated endocytosis. Endosomal acidification inhibitors like BafilomycinA1 and NH4Cl, which inhibit the CG pathway, reduce the uptake of RBD and impede Spike-pseudoviral infection in both AGS and AGS-ACE2 cells. The inhibition by BafilomycinA1 was found to be distinct from Chloroquine which neither affects RBD uptake nor alters endosomal pH, yet attenuates Spike-pseudovirus entry. By screening a subset of FDA-approved inhibitors for functionality similar to BafilomycinA1, we identified Niclosamide as a SARS-CoV-2 entry inhibitor. Further validation using a clinical isolate of SARS-CoV-2 in AGS-ACE2 and Vero cells confirmed its antiviral effect. We propose that Niclosamide, and other drugs which neutralize endosomal pH as well as inhibit the endocytic uptake, could provide broader applicability in subverting infection of viruses entering host cells via a pH-dependent endocytic pathway.


Subject(s)
COVID-19/drug therapy , COVID-19/virology , SARS-CoV-2/drug effects , SARS-CoV-2/pathogenicity , Virus Internalization/drug effects , Ammonium Chloride/pharmacology , Angiotensin-Converting Enzyme 2/genetics , Angiotensin-Converting Enzyme 2/physiology , Animals , Antiviral Agents/administration & dosage , Antiviral Agents/pharmacology , Cell Line , Chlorocebus aethiops , Chloroquine/pharmacology , Clathrin/metabolism , Drug Synergism , Endocytosis/drug effects , Endocytosis/physiology , Endosomes/drug effects , Endosomes/metabolism , Humans , Hydrogen-Ion Concentration/drug effects , Hydroxychloroquine/administration & dosage , Macrolides/pharmacology , Niclosamide/administration & dosage , Niclosamide/pharmacology , Protein Binding/drug effects , Protein Domains , SARS-CoV-2/physiology , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/physiology , Vero Cells
13.
Int J Mol Sci ; 22(13)2021 Jun 23.
Article in English | MEDLINE | ID: covidwho-1282516

ABSTRACT

The SARS-CoV-2 virus utilizes angiotensin converting enzyme (ACE-2) for cell entry and infection. This enzyme has important functions in the renin-angiotensin aldosterone system to preserve cardiovascular function. In addition to the heart, it is expressed in many tissues including the lung, intestines, brain, and kidney, however, its functions in these organs are mostly unknown. ACE-2 has membrane-bound and soluble forms. Its expression levels are altered in disease states and by a variety of medications. Currently, it is not clear how altered ACE-2 levels influence ACE-2 virulence and relevant complications. In addition, membrane-bound and soluble forms are thought to have different effects. Most work on this topic in the literature is on the SARS-CoV virus that has a high genetic resemblance to SARS-Co-V-2 and also uses ACE-2 enzyme to enter the cell, but with much lower affinity. More recent studies on SARS-CoV-2 are mainly clinical studies aiming at relating the effect of medications that are thought to influence ACE-2 levels, with COVID-19 outcomes for patients under these medications. This review paper aims to summarize what is known about the relationship between ACE-2 levels and SARS-CoV/SARS-CoV-2 virulence under altered ACE-2 expression states.


Subject(s)
Angiotensin-Converting Enzyme 2/physiology , COVID-19/physiopathology , COVID-19/virology , SARS-CoV-2/pathogenicity , Angiotensin-Converting Enzyme 2/chemistry , Angiotensin-Converting Enzyme Inhibitors , Host Microbial Interactions , Humans , Lung/metabolism , Virulence
14.
Cells ; 10(6)2021 06 12.
Article in English | MEDLINE | ID: covidwho-1270010

ABSTRACT

Coronavirus disease 2019 (COVID-19), a global pandemic, is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Angiotensin-converting enzyme 2 (ACE2) is the receptor for SARS-CoV-2 and transmembrane serine protease 2 (TMPRSS2) facilitates ACE2-mediated virus entry. Moreover, the expression of ACE2 in the testes of infertile men is higher than normal, which indicates that infertile men may be susceptible to be infected and SARS-CoV-2 may cause reproductive disorder through the pathway induced by ACE2 and TMPRSS2. Little is known about the pathway regulation of ACE2 and TMPRSS2 expression in male reproductive disorder. Since the regulation of gene expression is mediated by microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) at the post-transcriptional level, the aim of this study was to analyze the dysregulated miRNA-lncRNA interactions of ACE2 and TMPRSS2 in male reproductive disorder. Using bioinformatics analysis, we speculate that the predicted miRNAs including miR-125a-5p, miR-125b-5p, miR-574-5p, and miR-936 as regulators of ACE2 and miR-204-5p as a modulator of TMPRSS2 are associated with male infertility. The lncRNAs with a tissue-specific expression for testis including GRM7-AS3, ARHGAP26-AS1, BSN-AS1, KRBOX1-AS1, CACNA1C-IT3, AC012361.1, FGF14-IT1, AC012494.1, and GS1-24F4.2 were predicted. The identified miRNAs and lncRNAs are proposed as potential biomarkers to study the possible association between COVID-19 and male infertility. This study encourages further studies of miRNA-lncRNA interactions to explain the molecular mechanisms of male infertility in COVID-19 patients.


Subject(s)
COVID-19/complications , Gene Regulatory Networks , Infertility, Male/virology , MicroRNAs/genetics , RNA, Long Noncoding/genetics , Adult , Angiotensin-Converting Enzyme 2/physiology , COVID-19/genetics , Computational Biology/methods , Computer Simulation , Gene-Environment Interaction , Humans , Infertility, Male/genetics , Male , MicroRNAs/metabolism , RNA, Long Noncoding/metabolism , SARS-CoV-2/physiology , Serine Endopeptidases/physiology , Testis/metabolism , Testis/pathology , Testis/virology , Virus Internalization
15.
Int J Biol Sci ; 17(8): 1925-1939, 2021.
Article in English | MEDLINE | ID: covidwho-1266906

ABSTRACT

Background: Angiotensin-converting enzyme 2 (ACE2) and transmembrane serine protease 2 (TMPRSS2) allow entry of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) into host cells and play essential roles in cancer therapy. However, the functions of ACE2 and TMPRSS2 in kidney cancer remain unclear, especially as kidneys are targets for SARS-CoV-2 infection. Methods: UCSC Xena project, the Cancer Genome Atlas (TCGA), and Gene Expression Omnibus (GEO) databases (GSE30589 and GSE59185) were searched for gene expression in human tissues, gene expression data, and clinical information. Several bioinformatics methods were utilized to analyze the correlation between ACE2 and TMPRSS2 with respect to the prognosis of kidney renal clear cell carcinoma (KIRC) and kidney renal papillary cell carcinoma (KIRP). Results: ACE2 expression was significantly upregulated in tumor tissue, while its downregulation was associated with low survival in KIRC and KIRP patients. TMPRSS2 was downregulated in KIRC and KIRP, and its expression was not correlated with patient survival. According to clinical risk factor-based prediction models, ACE2 exhibits predictive accuracy for kidney cancer prognosis and is correlated with metabolism and immune infiltration. In an animal model, ACE2 expression was remarkably downregulated in SARS-CoV-2-infected cells compared to in the control. Conclusion: ACE2 expression is highly correlated with various metabolic pathways and is involved in immune infiltration.it plays a crucial role than TMPRSS2 in diagnosing and prognosis of kidney cancer patients. The overlap in ACE2 expression between kidney cancer and SARS-CoV-2 infection suggests that patients with KIRC or KIRP are at high risk of developing serious symptoms.


Subject(s)
Angiotensin-Converting Enzyme 2/biosynthesis , COVID-19/complications , Carcinoma, Renal Cell/complications , Kidney Neoplasms/complications , Receptors, Virus/biosynthesis , SARS-CoV-2 , Adult , Aged , Angiotensin-Converting Enzyme 2/genetics , Angiotensin-Converting Enzyme 2/physiology , Animals , Carcinoma, Renal Cell/immunology , Carcinoma, Renal Cell/metabolism , Carcinoma, Renal Cell/mortality , Chlorocebus aethiops , Down-Regulation , Drug Resistance, Neoplasm , Female , Gene Expression Regulation, Neoplastic , Gene Regulatory Networks , Humans , Kaplan-Meier Estimate , Kidney Neoplasms/immunology , Kidney Neoplasms/metabolism , Kidney Neoplasms/mortality , Lymphocytes, Tumor-Infiltrating/immunology , Male , Middle Aged , Models, Animal , Neoplasm Proteins/biosynthesis , Neoplasm Proteins/genetics , Organ Specificity , Prognosis , Proportional Hazards Models , Receptors, Virus/genetics , Renin-Angiotensin System/physiology , Serine Endopeptidases/biosynthesis , Serine Endopeptidases/genetics , Serine Endopeptidases/physiology , Tissue Array Analysis , Vero Cells
16.
Cells ; 10(6)2021 06 08.
Article in English | MEDLINE | ID: covidwho-1264419

ABSTRACT

In late 2019, the betacoronavirus SARS-CoV-2 was identified as the viral agent responsible for the coronavirus disease 2019 (COVID-19) pandemic. Coronaviruses Spike proteins are responsible for their ability to interact with host membrane receptors and different proteins have been identified as SARS-CoV-2 interactors, among which Angiotensin-converting enzyme 2 (ACE2), and Basigin2/EMMPRIN/CD147 (CD147). CD147 plays an important role in human immunodeficiency virus type 1, hepatitis C virus, hepatitis B virus, Kaposi's sarcoma-associated herpesvirus, and severe acute respiratory syndrome coronavirus infections. In particular, SARS-CoV recognizes the CD147 receptor expressed on the surface of host cells by its nucleocapsid protein binding to cyclophilin A (CyPA), a ligand for CD147. However, the involvement of CD147 in SARS-CoV-2 infection is still debated. Interference with both the function (blocking antibody) and the expression (knock down) of CD147 showed that this receptor partakes in SARS-CoV-2 infection and provided additional clues on the underlying mechanism: CD147 binding to CyPA does not play a role; CD147 regulates ACE2 levels and both receptors are affected by virus infection. Altogether, these findings suggest that CD147 is involved in SARS-CoV-2 tropism and represents a possible therapeutic target to challenge COVID-19.


Subject(s)
Angiotensin-Converting Enzyme 2/physiology , Basigin/physiology , SARS-CoV-2/physiology , Virus Internalization , A549 Cells , Angiotensin-Converting Enzyme 2/metabolism , Animals , Basigin/antagonists & inhibitors , Basigin/genetics , COVID-19/pathology , COVID-19/prevention & control , COVID-19/virology , Caco-2 Cells , Cell Line , Chlorocebus aethiops , Hep G2 Cells , Host-Pathogen Interactions , Humans , Molecular Targeted Therapy , RNA Interference/physiology , RNA, Small Interfering/pharmacology , RNA, Small Interfering/therapeutic use , Receptors, Virus/metabolism , Receptors, Virus/physiology , SARS-CoV-2/metabolism , Vero Cells , Viral Tropism/physiology
18.
Cells ; 10(6)2021 06 07.
Article in English | MEDLINE | ID: covidwho-1259431

ABSTRACT

Coronaviruses such as SARS-CoV-2, which is responsible for COVID-19, depend on virus spike protein binding to host cell receptors to cause infection. The SARS-CoV-2 spike protein binds primarily to ACE2 on target cells and is then processed by membrane proteases, including TMPRSS2, leading to viral internalisation or fusion with the plasma membrane. It has been suggested, however, that receptors other than ACE2 may be involved in virus binding. We have investigated the interactions of recombinant versions of the spike protein with human epithelial cell lines that express low/very low levels of ACE2 and TMPRSS2 in a proxy assay for interaction with host cells. A tagged form of the spike protein containing the S1 and S2 regions bound in a temperature-dependent manner to all cell lines, whereas the S1 region alone and the receptor-binding domain (RBD) interacted only weakly. Spike protein associated with cells independently of ACE2 and TMPRSS2, while RBD required the presence of high levels of ACE2 for interaction. As the spike protein has previously been shown to bind heparin, a soluble glycosaminoglycan, we tested the effects of various heparins on ACE2-independent spike protein interaction with cells. Unfractionated heparin inhibited spike protein interaction with an IC50 value of <0.05 U/mL, whereas two low-molecular-weight heparins were less effective. A mutant form of the spike protein, lacking the arginine-rich putative furin cleavage site, interacted only weakly with cells and had a lower affinity for unfractionated and low-molecular-weight heparin than the wild-type spike protein. This suggests that the furin cleavage site might also be a heparin-binding site and potentially important for interactions with host cells. The glycosaminoglycans heparan sulphate and dermatan sulphate, but not chondroitin sulphate, also inhibited the binding of spike protein, indicating that it might bind to one or both of these glycosaminoglycans on the surface of target cells.


Subject(s)
Angiotensin-Converting Enzyme 2/physiology , Epithelial Cells/metabolism , Heparin/pharmacology , Spike Glycoprotein, Coronavirus/metabolism , A549 Cells , Angiotensin-Converting Enzyme 2/genetics , Animals , Binding Sites/drug effects , Binding Sites/genetics , Caco-2 Cells , Cell Line , Chlorocebus aethiops , Dermatan Sulfate/pharmacology , Down-Regulation/drug effects , Epithelial Cells/drug effects , Epithelial Cells/virology , Glycosaminoglycans/pharmacology , HEK293 Cells , HaCaT Cells , Heparitin Sulfate/pharmacology , Humans , Protein Binding/drug effects , Protein Binding/genetics , SARS-CoV-2/drug effects , SARS-CoV-2/physiology , Spike Glycoprotein, Coronavirus/chemistry , Vero Cells , Virus Internalization/drug effects
19.
Clin J Am Soc Nephrol ; 16(7): 1061-1072, 2021 07.
Article in English | MEDLINE | ID: covidwho-1259309

ABSTRACT

BACKGROUND AND OBJECTIVES: There is concern about potential deleterious effects of angiotensin-converting enzyme inhibitors (ACEis) and angiotensin II receptor blockers (ARBs) in patients with coronavirus disease 2019 (COVID-19). Patients with kidney failure, who often use ACEis/ARBs, are at higher risk of more severe COVID-19. However, there are no data available on the association of ACEi/ARB use with COVID-19 severity in this population. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: From the European Renal Association COVID-19 database (ERACODA), we retrieved data on kidney transplant recipients and patients on dialysis who were affected by COVID-19, between February 1 and October 1, 2020, and had information on 28-day mortality. We used Cox proportional-hazards regression to calculate hazard ratios for the association between ACEi/ARB use and 28-day mortality risk. Additionally, we studied the association of discontinuation of these agents with 28-day mortality. RESULTS: We evaluated 1511 patients: 459 kidney transplant recipients and 1052 patients on dialysis. At diagnosis of COVID-19, 189 (41%) of the transplant recipients and 288 (27%) of the patients on dialysis were on ACEis/ARBs. A total of 88 (19%) transplant recipients and 244 (23%) patients on dialysis died within 28 days of initial presentation. In both groups of patients, there was no association between ACEi/ARB use and 28-day mortality in both crude and adjusted models (in transplant recipients, adjusted hazard ratio, 1.12; 95% confidence interval [95% CI], 0.69 to 1.83; in patients on dialysis, adjusted hazard ratio, 1.04; 95% CI, 0.73 to 1.47). Among transplant recipients, ACEi/ARB discontinuation was associated with a higher mortality risk after adjustment for demographics and comorbidities, but the association was no longer statistically significant after adjustment for severity of COVID-19 (adjusted hazard ratio, 1.36; 95% CI, 0.40 to 4.58). Among patients on dialysis, ACEi/ARB discontinuation was not associated with mortality in any model. We obtained similar results across subgroups when ACEis and ARBs were studied separately, and when other outcomes for severity of COVID-19 were studied, e.g., hospital admission, admission to the intensive care unit, or need for ventilator support. CONCLUSIONS: Among kidney transplant recipients and patients on dialysis with COVID-19, there was no significant association of ACEi/ARB use or discontinuation with mortality.


Subject(s)
Angiotensin Receptor Antagonists/adverse effects , Angiotensin-Converting Enzyme Inhibitors/adverse effects , COVID-19/mortality , Renal Insufficiency/complications , SARS-CoV-2 , Aged , Aged, 80 and over , Angiotensin-Converting Enzyme 2/physiology , Female , Hospitalization , Humans , Kidney Transplantation , Male , Middle Aged , Proportional Hazards Models
20.
Blood ; 138(4): 344-349, 2021 07 29.
Article in English | MEDLINE | ID: covidwho-1255893

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is associated with the hypercoagulable state. Tissue factor (TF) is the primary cellular initiator of coagulation. Most of the TF expressed on cell surfaces remains cryptic. Sphingomyelin (SM) is responsible for maintaining TF in the encrypted state, and hydrolysis of SM by acid sphingomyelinase (ASMase) increases TF activity. ASMase was shown to play a role in virus infection biology. In the present study, we investigated the role of ASMase in SARS-CoV-2 infection-induced TF procoagulant activity. Infection of human monocyte-derived macrophages (MDMs) with SARS-CoV-2 spike protein pseudovirus (SARS-CoV-2-SP-PV) markedly increased TF procoagulant activity at the cell surface and released TF+ extracellular vesicles. The pseudovirus infection did not increase either TF protein expression or phosphatidylserine externalization. SARS-CoV-2-SP-PV infection induced the translocation of ASMase to the outer leaflet of the plasma membrane, which led to the hydrolysis of SM in the membrane. Pharmacologic inhibitors or genetic silencing of ASMase attenuated SARS-CoV-2-SP-PV-induced increased TF activity. Inhibition of the SARS-CoV-2 receptor, angiotensin-converting enzyme-2, attenuated SARS-CoV-2-SP-PV-induced increased TF activity. Overall, our data suggest that SARS-CoV-2 infection activates the coagulation by decrypting TF through activation of ASMase. Our data suggest that the US Food and Drug Administration-approved functional inhibitors of ASMase may help treat hypercoagulability in patients with COVID-19.


Subject(s)
COVID-19/blood , Macrophages/virology , Membrane Proteins/physiology , SARS-CoV-2 , Sphingomyelin Phosphodiesterase/physiology , Spike Glycoprotein, Coronavirus/physiology , Thrombophilia/etiology , Thromboplastin/physiology , Angiotensin-Converting Enzyme 2/physiology , COVID-19/complications , Cell-Derived Microparticles , Enzyme Activation , Humans , Hydrolysis , Macrophages/enzymology , Molecular Targeted Therapy , Plasmids , Protein Transport , RNA Interference , RNA, Small Interfering/genetics , Receptors, Virus/physiology , Sphingomyelin Phosphodiesterase/antagonists & inhibitors , Sphingomyelins/physiology , Thrombophilia/blood , Thrombophilia/drug therapy , Thrombophilia/enzymology
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