Your browser doesn't support javascript.
Show: 20 | 50 | 100
Results 1 - 20 de 22
Filter
1.
Cell Mol Biol Lett ; 27(1): 10, 2022 Feb 02.
Article in English | MEDLINE | ID: covidwho-1753103

ABSTRACT

The novel coronavirus disease 2019 (COVID-19) pandemic has spread worldwide, and finding a safe therapeutic strategy and effective vaccine is critical to overcoming severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Therefore, elucidation of pathogenesis mechanisms, especially entry routes of SARS-CoV-2 may help propose antiviral drugs and novel vaccines. Several receptors have been demonstrated for the interaction of spike (S) protein of SARS-CoV-2 with host cells, including angiotensin-converting enzyme (ACE2), ephrin ligands and Eph receptors, neuropilin 1 (NRP-1), P2X7, and CD147. The expression of these entry receptors in the central nervous system (CNS) may make the CNS prone to SARS-CoV-2 invasion, leading to neurodegenerative diseases. The present review provides potential pathological mechanisms of SARS-CoV-2 infection in the CNS, including entry receptors and cytokines involved in neuroinflammatory conditions. Moreover, it explains several neurodegenerative disorders associated with COVID-19. Finally, we suggest inflammasome and JaK inhibitors as potential therapeutic strategies for neurodegenerative diseases.


Subject(s)
COVID-19/drug therapy , Central Nervous System/drug effects , Inflammasomes/drug effects , Neurodegenerative Diseases/drug therapy , Receptors, Virus/genetics , SARS-CoV-2/drug effects , Virus Internalization/drug effects , Angiotensin-Converting Enzyme 2/genetics , Angiotensin-Converting Enzyme 2/metabolism , Antiviral Agents/therapeutic use , Basigin/genetics , Basigin/metabolism , COVID-19/genetics , COVID-19/metabolism , COVID-19/virology , Central Nervous System/metabolism , Central Nervous System/virology , Ephrins/genetics , Ephrins/metabolism , Gene Expression Regulation , Host-Pathogen Interactions/drug effects , Host-Pathogen Interactions/genetics , Humans , Immunologic Factors/therapeutic use , Inflammasomes/genetics , Inflammasomes/metabolism , Janus Kinase Inhibitors/therapeutic use , Janus Kinases/antagonists & inhibitors , Janus Kinases/genetics , Janus Kinases/metabolism , Neurodegenerative Diseases/genetics , Neurodegenerative Diseases/metabolism , Neurodegenerative Diseases/virology , Neuropilin-1/genetics , Neuropilin-1/metabolism , Receptors, Purinergic P2X7/genetics , Receptors, Purinergic P2X7/metabolism , Receptors, Virus/antagonists & inhibitors , Receptors, Virus/metabolism , SARS-CoV-2/genetics , SARS-CoV-2/metabolism , SARS-CoV-2/pathogenicity , Signal Transduction
2.
Chem Biol Interact ; 353: 109796, 2022 Feb 01.
Article in English | MEDLINE | ID: covidwho-1611644

ABSTRACT

Coronavirus disease 2019 (COVID-19) was declared a serious global public health emergency. Hospitalization and mortality rates of lung cancer patients diagnosed with COVID-19 are higher than those of patients presenting with other cancers. However, the reasons for the outcomes being disproportionately severe in lung adenocarcinoma (LUAD) patients with COVID-19 remain elusive. The present study aimed to identify the possible causes for disproportionately severe COVID-19 outcomes in LUAD patients and determine a therapeutic target for COVID-19 patients with LUAD. We used publicly available data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases and various bioinformatics tools to identify and analyze the genes implicated in SARS-CoV-2 infection in LUAD patients. Upregulation of the SARS-CoV-2 infection-related molecules dipeptidyl peptidase 4, basigin, cathepsin B (CTSB), methylenetetrahydrofolate dehydrogenase, and peptidylprolyl isomerase B rather than angiotensin-converting enzyme 2 may explain the relatively high susceptibility of LUAD patients to SARS-CoV-2 infection. CTSB was highly expressed in the LUAD tissues after SARS-CoV-2 infection, and its expression was positively correlated with immune cell infiltration and proinflammatory cytokine expression. These findings suggest that CTSB plays a vital role in the hyperinflammatory response in COVID-19 patients with LUAD and is a promising target for the development of a novel drug therapy for COVID-19 patients.


Subject(s)
Adenocarcinoma of Lung/virology , COVID-19/genetics , Cathepsin B/genetics , Lung Neoplasms/virology , Adenocarcinoma of Lung/genetics , Adenocarcinoma of Lung/immunology , Adenocarcinoma of Lung/mortality , Angiotensin-Converting Enzyme 2/genetics , Animals , Basigin/genetics , CD8-Positive T-Lymphocytes/virology , COVID-19/immunology , COVID-19/mortality , Cricetinae , Cyclophilins/genetics , Cytokines/blood , Dipeptidyl Peptidase 4/genetics , Gene Expression Regulation, Neoplastic , Humans , Lung Neoplasms/genetics , Lung Neoplasms/immunology , Lung Neoplasms/mortality , Methylenetetrahydrofolate Dehydrogenase (NADP)/genetics , Minor Histocompatibility Antigens/genetics , Molecular Targeted Therapy , Prognosis , Protein Interaction Maps/genetics , Up-Regulation
3.
FASEB J ; 35(12): e21969, 2021 12.
Article in English | MEDLINE | ID: covidwho-1532548

ABSTRACT

Several evidence suggests that, in addition to the respiratory tract, also the gastrointestinal tract is a main site of severe acute respiratory syndrome CoronaVirus 2 (SARS-CoV-2) infection, as an example of a multi-organ vascular damage, likely associated with poor prognosis. To assess mechanisms SARS-CoV-2 responsible of tissue infection and vascular injury, correlating with thrombotic damage, specimens of the digestive tract positive for SARS-CoV-2 nucleocapsid protein were analyzed deriving from three patients, negative to naso-oro-pharyngeal swab for SARS-CoV-2. These COVID-19-negative patients came to clinical observation due to urgent abdominal surgery that removed different sections of the digestive tract after thrombotic events. Immunohistochemical for the expression of SARS-CoV-2 combined with a panel of SARS-CoV-2 related proteins angiotensin-converting enzyme 2 receptor, cluster of differentiation 147 (CD147), human leukocyte antigen-G (HLA-G), vascular endothelial growth factor (VEGF) and matrix metalloproteinase-9 was performed. Tissue samples were also evaluated by electron microscopy for ultrastructural virus localization and cell characterization. The damage of the tissue was assessed by ultrastructural analysis. It has been observed that CD147 expression levels correlate with SARS-CoV-2 infection extent, vascular damage and an increased expression of VEGF and thrombosis. The confirmation of CD147 co-localization with SARS-CoV-2 Spike protein binding on gastrointestinal tissues and the reduction of the infection level in intestinal epithelial cells after CD147 neutralization, suggest CD147 as a possible key factor for viral susceptibility of gastrointestinal tissue. The presence of SARS-CoV-2 infection of gastrointestinal tissue might be consequently implicated in abdominal thrombosis, where VEGF might mediate the vascular damage.


Subject(s)
Basigin/metabolism , COVID-19/complications , Digestive System Diseases/pathology , SARS-CoV-2/isolation & purification , Spike Glycoprotein, Coronavirus/metabolism , Thrombosis/pathology , Vascular Endothelial Growth Factor A/metabolism , Aged , Basigin/genetics , COVID-19/virology , Digestive System Diseases/genetics , Digestive System Diseases/metabolism , Digestive System Diseases/virology , Female , Humans , Male , Middle Aged , Prognosis , Spike Glycoprotein, Coronavirus/genetics , Thrombosis/genetics , Thrombosis/metabolism , Thrombosis/virology , Vascular Endothelial Growth Factor A/genetics
4.
Signal Transduct Target Ther ; 6(1): 347, 2021 09 25.
Article in English | MEDLINE | ID: covidwho-1437669

ABSTRACT

SARS-CoV-2 mutations contribute to increased viral transmissibility and immune escape, compromising the effectiveness of existing vaccines and neutralizing antibodies. An in-depth investigation on COVID-19 pathogenesis is urgently needed to develop a strategy against SARS-CoV-2 variants. Here, we identified CD147 as a universal receptor for SARS-CoV-2 and its variants. Meanwhile, Meplazeumab, a humanized anti-CD147 antibody, could block cellular entry of SARS-CoV-2 and its variants-alpha, beta, gamma, and delta, with inhibition rates of 68.7, 75.7, 52.1, 52.1, and 62.3% at 60 µg/ml, respectively. Furthermore, humanized CD147 transgenic mice were susceptible to SARS-CoV-2 and its two variants, alpha and beta. When infected, these mice developed exudative alveolar pneumonia, featured by immune responses involving alveoli-infiltrated macrophages, neutrophils, and lymphocytes and activation of IL-17 signaling pathway. Mechanistically, we proposed that severe COVID-19-related cytokine storm is induced by a "spike protein-CD147-CyPA signaling axis": Infection of SARS-CoV-2 through CD147 initiated the JAK-STAT pathway, which further induced expression of cyclophilin A (CyPA); CyPA reciprocally bound to CD147 and triggered MAPK pathway. Consequently, the MAPK pathway regulated the expression of cytokines and chemokines, which promoted the development of cytokine storm. Importantly, Meplazumab could effectively inhibit viral entry and inflammation caused by SARS-CoV-2 and its variants. Therefore, our findings provided a new perspective for severe COVID-19-related pathogenesis. Furthermore, the validated universal receptor for SARS-CoV-2 and its variants can be targeted for COVID-19 treatment.


Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , Antibodies, Monoclonal, Humanized/pharmacology , Basigin/antagonists & inhibitors , Basigin/metabolism , COVID-19/drug therapy , COVID-19/metabolism , Cytokine Release Syndrome/drug therapy , SARS-CoV-2/metabolism , Angiotensin-Converting Enzyme 2/genetics , Animals , Basigin/genetics , COVID-19/genetics , Chlorocebus aethiops , Cytokine Release Syndrome/genetics , Cytokine Release Syndrome/metabolism , Humans , MAP Kinase Signaling System/drug effects , MAP Kinase Signaling System/genetics , Mice , Mice, Transgenic , SARS-CoV-2/genetics , Vero Cells
5.
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
6.
Respir Res ; 22(1): 164, 2021 May 29.
Article in English | MEDLINE | ID: covidwho-1247590

ABSTRACT

BACKGROUND: Chronic obstructive pulmonary disease (COPD) patients are at increased risk of poor outcome from Coronavirus disease (COVID-19). Early data suggest elevated Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) receptor angiotensin converting enzyme 2 (ACE2) expression, but relationships to disease phenotype and downstream regulators of inflammation in the Renin-Angiotensin system (RAS) are unknown. We aimed to determine the relationship between RAS gene expression relevant to SARS-CoV-2 infection in the lung with disease characteristics in COPD, and the regulation of newly identified SARS-CoV-2 receptors and spike-cleaving proteases, important for SARS-CoV-2 infection. METHODS: We quantified gene expression using RNA sequencing of epithelial brushings and bronchial biopsies from 31 COPD and 37 control subjects. RESULTS: ACE2 gene expression (log2-fold change (FC)) was increased in COPD compared to ex-smoking (HV-ES) controls in epithelial brushings (0.25, p = 0.042) and bronchial biopsies (0.23, p = 0.050), and correlated with worse lung function (r = - 0.28, p = 0.0090). ACE2 was further increased in frequent exacerbators compared to infrequent exacerbators (0.51, p = 0.00045) and associated with use of ACE inhibitors (ACEi) (0.50, p = 0.0034), having cardiovascular disease (0.23, p = 0.048) or hypertension (0.34, p = 0.0089), and inhaled corticosteroid use in COPD subjects in bronchial biopsies (0.33, p = 0.049). Angiotensin II receptor type (AGTR)1 and 2 expression was decreased in COPD bronchial biopsies compared to HV-ES controls with log2FC of -0.26 (p = 0.033) and - 0.40, (p = 0.0010), respectively. However, the AGTR1:2 ratio was increased in COPD subjects compared with HV-ES controls, log2FC of 0.57 (p = 0.0051). Basigin, a newly identified potential SARS-CoV-2 receptor was also upregulated in both brushes, log2FC of 0.17 (p = 0.0040), and bronchial biopsies, (log2FC of 0.18 (p = 0.017), in COPD vs HV-ES. Transmembrane protease, serine (TMPRSS)2 was not differentially regulated between control and COPD. However, various other spike-cleaving proteases were, including TMPRSS4 and Cathepsin B, in both epithelial brushes (log2FC of 0.25 (p = 0.0012) and log2FC of 0.56 (p = 5.49E-06), respectively) and bronchial biopsies (log2FC of 0.49 (p = 0.00021) and log2FC of 0.246 (p = 0.028), respectively). CONCLUSION: This study identifies key differences in expression of genes related to susceptibility and aetiology of COVID-19 within the COPD lung. Further studies to understand the impact on clinical course of disease are now required.


Subject(s)
COVID-19/genetics , Lung/metabolism , Pulmonary Disease, Chronic Obstructive/genetics , Transcriptome , Aged , Angiotensin-Converting Enzyme 2/genetics , Angiotensin-Converting Enzyme 2/metabolism , Basigin/genetics , Basigin/metabolism , COVID-19/diagnosis , COVID-19/metabolism , COVID-19/physiopathology , Case-Control Studies , Female , Forced Expiratory Volume , Gene Expression Regulation , Humans , Lung/physiopathology , Male , Middle Aged , Prognosis , Pulmonary Disease, Chronic Obstructive/diagnosis , Pulmonary Disease, Chronic Obstructive/metabolism , Pulmonary Disease, Chronic Obstructive/physiopathology , Receptor, Angiotensin, Type 1/genetics , Receptor, Angiotensin, Type 1/metabolism , Receptor, Angiotensin, Type 2/genetics , Receptor, Angiotensin, Type 2/metabolism , Vital Capacity
7.
J Biol Chem ; 297(1): 100847, 2021 07.
Article in English | MEDLINE | ID: covidwho-1246014

ABSTRACT

The zoonotic transmission of highly pathogenic coronaviruses into the human population is a pressing concern highlighted by the ongoing SARS-CoV-2 pandemic. Recent work has helped to illuminate much about the mechanisms of SARS-CoV-2 entry into the cell, which determines host- and tissue-specific tropism, pathogenicity, and zoonotic transmission. Here we discuss current findings on the factors governing SARS-CoV-2 entry. We first reviewed key features of the viral spike protein (S) mediating fusion of the viral envelope and host cell membrane through binding to the SARS-CoV-2 receptor, angiotensin-converting enzyme 2. We then examined the roles of host proteases including transmembrane protease serine 2 and cathepsins in processing S for virus entry and the impact of this processing on endosomal and plasma membrane virus entry routes. We further discussed recent work on several host cofactors that enhance SARS-CoV-2 entry including Neuropilin-1, CD147, phosphatidylserine receptors, heparan sulfate proteoglycans, sialic acids, and C-type lectins. Finally, we discussed two key host restriction factors, i.e., interferon-induced transmembrane proteins and lymphocyte antigen 6 complex locus E, which can disrupt SARS-CoV-2 entry. The features of SARS-CoV-2 are presented in the context of other human coronaviruses, highlighting unique aspects. In addition, we identify the gaps in understanding of SARS-CoV-2 entry that will need to be addressed by future studies.


Subject(s)
COVID-19/metabolism , SARS-CoV-2/physiology , Virus Internalization , Animals , Basigin/genetics , Basigin/metabolism , COVID-19/genetics , COVID-19/virology , Host-Pathogen Interactions , Humans , Lectins, C-Type/genetics , Lectins, C-Type/metabolism , Neuropilin-1/genetics , Neuropilin-1/metabolism , Receptors, Virus/genetics , Receptors, Virus/metabolism , SARS-CoV-2/genetics
8.
J Pathol Clin Res ; 7(5): 446-458, 2021 09.
Article in English | MEDLINE | ID: covidwho-1224964

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) poses a serious threat to healthcare systems worldwide. Binding of the virus to angiotensin-converting enzyme 2 (ACE2) is an important step in the infection mechanism. However, it is unknown if ACE2 expression in patients with chronic lung diseases (CLDs), such as chronic obstructive pulmonary disease (COPD), idiopathic pulmonary arterial hypertension (IPAH), or pulmonary fibrosis (PF), is changed as compared to controls. We used lung samples from patients with COPD (n = 28), IPAH (n = 10), and PF (n = 10) as well as healthy control donor (n = 10) tissue samples to investigate the expression of ACE2 and related cofactors that might influence the course of SARS-CoV-2 infection. Expression levels of the ACE2 receptor, the putative receptor CD147/BSG, and the viral entry cofactors TMPRSS2 (transmembrane serine protease 2), EZR, and FURIN were determined by quantitative PCR and in open-access RNA sequencing datasets. Immunohistochemical and single-cell RNA sequencing (scRNAseq) analyses were used for localization and coexpression, respectively. Soluble ACE2 (sACE2) plasma levels were analyzed by enzyme-linked immunosorbent assay. In COPD as compared to donor, IPAH, and PF lung tissue, gene expression of ACE2, TMPRSS2, and EZR was significantly elevated, but circulating sACE2 levels were significantly reduced in COPD and PF plasma compared to healthy control and IPAH plasma samples. Lung tissue expressions of FURIN and CD147/BSG were downregulated in COPD. None of these changes were associated with changes in pulmonary hemodynamics. Histological analysis revealed coexpression of ACE2, TMPRSS2, and Ezrin in bronchial regions and epithelial cells. This was confirmed by scRNAseq analysis. There were no significant expression changes of the analyzed molecules in the lung tissue of IPAH and idiopathic PF as compared to control. In conclusion, we reveal increased ACE2 and TMPRSS2 expression in lung tissue with a concomitant decrease of protective sACE2 in COPD patients. These changes represent the possible risk factors for an increased susceptibility of COPD patients to SARS-CoV-2 infection.


Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , COVID-19/pathology , Familial Primary Pulmonary Hypertension/pathology , Idiopathic Pulmonary Fibrosis/pathology , Pulmonary Disease, Chronic Obstructive/pathology , SARS-CoV-2/physiology , Serine Endopeptidases/metabolism , Adult , Aged , Angiotensin-Converting Enzyme 2/genetics , Basigin/genetics , Basigin/metabolism , COVID-19/metabolism , COVID-19/virology , Disease Susceptibility , Familial Primary Pulmonary Hypertension/enzymology , Familial Primary Pulmonary Hypertension/virology , Female , Furin/genetics , Furin/metabolism , Gene Expression Regulation , Humans , Idiopathic Pulmonary Fibrosis/metabolism , Idiopathic Pulmonary Fibrosis/virology , Lung/metabolism , Lung/pathology , Lung/virology , Male , Middle Aged , Pulmonary Disease, Chronic Obstructive/metabolism , Pulmonary Disease, Chronic Obstructive/virology , Risk Factors , Serine Endopeptidases/genetics , Virus Internalization
9.
Arch Virol ; 166(8): 2089-2108, 2021 Aug.
Article in English | MEDLINE | ID: covidwho-1209235

ABSTRACT

The SARS-CoV-2 pandemic has become one of the most serious health concerns globally. Although multiple vaccines have recently been approved for the prevention of coronavirus disease 2019 (COVID-19), an effective treatment is still lacking. Our knowledge of the pathogenicity of this virus is still incomplete. Studies have revealed that viral factors such as the viral load, duration of exposure to the virus, and viral mutations are important variables in COVID-19 outcome. Furthermore, host factors, including age, health condition, co-morbidities, and genetic background, might also be involved in clinical manifestations and infection outcome. This review focuses on the importance of variations in the host genetic background and pathogenesis of SARS-CoV-2. We will discuss the significance of polymorphisms in the ACE-2, TMPRSS2, vitamin D receptor, vitamin D binding protein, CD147, glucose-regulated protein 78 kDa, dipeptidyl peptidase-4 (DPP4), neuropilin-1, heme oxygenase, apolipoprotein L1, vitamin K epoxide reductase complex 1 (VKORC1), and immune system genes for the clinical outcome of COVID-19.


Subject(s)
COVID-19/genetics , ABO Blood-Group System/genetics , Angiotensin-Converting Enzyme 2/genetics , Apolipoprotein L1/genetics , Basigin/genetics , COVID-19/epidemiology , COVID-19/therapy , Dipeptidyl Peptidase 4/genetics , Heat-Shock Proteins/genetics , Heme Oxygenase-1/genetics , Humans , Immunity/genetics , Neuropilin-1/genetics , Patient Outcome Assessment , Polymorphism, Genetic , Receptors, Calcitriol/genetics , SARS-CoV-2 , Serine Endopeptidases/genetics , Vitamin D-Binding Protein/genetics , Vitamin K Epoxide Reductases/genetics
10.
Gac. méd. Méx ; 156(4): 324-329, Jul.-Aug. 2020. graf
Article in English | WHO COVID, LILACS (Americas) | ID: covidwho-1042995

ABSTRACT

Abstract In the efforts to explain COVID-19 pathophysiology, studies are being carried out on the correspondence between the expression of SARS-CoV-2 cell receptors and viral sequences. ACE2, CD147 and TMPRSS2 receptors expression could indicate poorly explored potential infection targets. For the genomic analysis of SARS-CoV-2 receptors, using BioGPS information was decided, which is a portal that centralizes genetic annotation resources, in combination with that of The Human Protein Atlas, the largest portal of human transcriptome and proteome data. We also reviewed the most recent articles on the subject. RNA and viral receptor proteins expression was observed in numerous anatomical sites, which partially coincides with the information reported in the literature. High expression in testicular cells markedly stood out, and it would be therefore important ruling out whether this anatomical site is a SARS-CoV-2 reservoir; otherwise, germ cell damage, as it is observed in infections with other RNA viruses, should be determined.


Resumen En el afán por explicar la fisiopatogenia de COVID-19 se están realizando estudios en torno a la correspondencia entre la expresión de receptores celulares de SARS-CoV-2 y las secuencias virales. La expresión de los receptores ACE2, CD147 y TMPRSS2 podría indicar blancos de infección poco explorados. Para el análisis genómico de los receptores de SARS-CoV-2 se optó por utilizar la información del BioGPS, un portal que centraliza los recursos de anotación genética, en combinación con la de The Human Protein Atlas, el portal más grande de datos del transcriptoma y proteoma humanos. También se revisaron los artículos más recientemente respecto al tema. En numerosos sitios anatómicos se observó la expresión de ARN y proteínas de los receptores del virus, que coinciden parcialmente con la información reportada en la literatura. Resaltó la alta expresión en las células de los testículos, por lo que sería importante descartar si este sitio anatómico es un reservorio de SARS-CoV-2; de no ser así, determinar el daño en las células germinales, tal como sucede en infecciones por otros virus ARN.


Subject(s)
Humans , Pneumonia, Viral/virology , Testis/virology , Coronavirus Infections/virology , Betacoronavirus/isolation & purification , Pneumonia, Viral/physiopathology , Serine Endopeptidases/genetics , Gene Expression Regulation , Virus Latency , Coronavirus Infections/physiopathology , Peptidyl-Dipeptidase A/genetics , Basigin/genetics , Pandemics , Angiotensin-Converting Enzyme 2 , SARS-CoV-2 , COVID-19
11.
Genes (Basel) ; 12(1)2020 12 25.
Article in English | MEDLINE | ID: covidwho-1021948

ABSTRACT

The human serine protease serine 2 TMPRSS2 is involved in the priming of proteins of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and represents a possible target for COVID-19 therapy. The TMPRSS2 gene may be co-expressed with SARS-CoV-2 cell receptor genes angiotensin-converting enzyme 2 (ACE2) and Basigin (BSG), but only TMPRSS2 demonstrates tissue-specific expression in alveolar cells according to single-cell RNA sequencing data. Our analysis of the structural variability of the TMPRSS2 gene based on genome-wide data from 76 human populations demonstrates that a functionally significant missense mutation in exon 6/7 in the TMPRSS2 gene is found in many human populations at relatively high frequencies, with region-specific distribution patterns. The frequency of the missense mutation encoded by rs12329760, which has previously been found to be associated with prostate cancer, ranged between 10% and 63% and was significantly higher in populations of Asian origin compared with European populations. In addition to single-nucleotide polymorphisms, two copy number variants were detected in the TMPRSS2 gene. A number of microRNAs have been predicted to regulate TMPRSS2 and BSG expression levels, but none of them is enriched in lung or respiratory tract cells. Several well-studied drugs can downregulate the expression of TMPRSS2 in human cells, including acetaminophen (paracetamol) and curcumin. Thus, the interactions of TMPRSS2 with SARS-CoV-2, together with its structural variability, gene-gene interactions, expression regulation profiles, and pharmacogenomic properties, characterize this gene as a potential target for COVID-19 therapy.


Subject(s)
COVID-19/drug therapy , COVID-19/therapy , Gene Expression Regulation, Enzymologic/drug effects , Molecular Targeted Therapy , SARS-CoV-2/physiology , Serine Endopeptidases/genetics , Acetaminophen/pharmacology , Acetaminophen/therapeutic use , Angiotensin-Converting Enzyme 2/antagonists & inhibitors , Angiotensin-Converting Enzyme 2/biosynthesis , Angiotensin-Converting Enzyme 2/genetics , Asia/epidemiology , Basigin/biosynthesis , Basigin/genetics , Basigin/physiology , COVID-19/ethnology , COVID-19/genetics , Curcumin/pharmacology , Curcumin/therapeutic use , Europe/epidemiology , Exons/genetics , Gene Frequency , Genetic Predisposition to Disease , Genetic Variation , Humans , MicroRNAs/genetics , Mutation, Missense , Pharmacogenomic Testing , Protein Interaction Mapping , Receptors, Virus/antagonists & inhibitors , Receptors, Virus/biosynthesis , Receptors, Virus/genetics , Serine Endopeptidases/biosynthesis , Serine Endopeptidases/physiology , Single-Cell Analysis , Spike Glycoprotein, Coronavirus/metabolism
12.
Stem Cell Rev Rep ; 17(1): 278-284, 2021 02.
Article in English | MEDLINE | ID: covidwho-1009199

ABSTRACT

In addition to a number of scientific and medical questions about SARS-CoV-2 infection that still need to be answered, there is also the question of how this highly virulent virus and COVID-19 disease affect gametogenesis in humans. Even more important is the question of whether the virus can also enter and infect oocytes and possibly alter them in an unknown way, which could also affect the development and status of the human embryo. The answers to these questions are still poorly known, so we reviewed the human oocyte transcriptome and proteome obtained in our previous studies and found that human oocytes from the in vitro fertilization program expressed both the ACE2 and BSG genes and the corresponding ACE2 and BSG proteins. This means that human oocytes possess the molecular 'machinery' to facilitate SARS-CoV-2 entrance and infection. According to various studies, especially in animal models, different viruses can infect oocytes, so infection of the oocyte with SARS-Cov-2 cannot be completely ruled out. A hypothetical model of human oocyte infection with this virus has been proposed.


Subject(s)
Angiotensin-Converting Enzyme 2/genetics , Basigin/genetics , COVID-19/genetics , Oocytes/virology , COVID-19/virology , Embryonic Development/genetics , Gametogenesis/genetics , Gene Expression Regulation, Developmental/genetics , Humans , Oocytes/growth & development , Oocytes/pathology , SARS-CoV-2/pathogenicity
13.
FEBS J ; 287(17): 3677-3680, 2020 09.
Article in English | MEDLINE | ID: covidwho-960856

ABSTRACT

Coronavirus disease 2019 (COVID-19), the highly contagious illness caused by a novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has spread across the globe, becoming one of the most challenging public health crisis of our times. SARS-CoV-2 can cause severe disease associated with multiple organ damage. Cancer patients have a higher risk of SARS-CoV-2 infection and death. While the virus uses angiotensin-converting enzyme 2 (ACE2) as the primary entry receptor, the recent experimental and clinical findings suggest that some tumor markers, including CD147 (basigin), can provide an additional entry for SARS-CoV-2 infection through binding to the viral spike (S) protein. In the absence of specific viral drugs, blocking of CD147 might be a way to prevent virus invasion. Identifying other target proteins is of high importance as targeting the alternative receptors for SARS-CoV-2 might open up a promising avenue for the treatment of COVID-19 patients, including those who have cancer.


Subject(s)
Antineoplastic Agents, Immunological/therapeutic use , Basigin/antagonists & inhibitors , Biomarkers, Tumor/antagonists & inhibitors , COVID-19/drug therapy , Neoplasms/drug therapy , Spike Glycoprotein, Coronavirus/antagonists & inhibitors , Angiotensin-Converting Enzyme 2/genetics , Angiotensin-Converting Enzyme 2/metabolism , Antibodies, Monoclonal/therapeutic use , Antibodies, Monoclonal, Humanized/therapeutic use , Basigin/genetics , Basigin/immunology , Biomarkers, Tumor/genetics , Biomarkers, Tumor/immunology , COVID-19/genetics , COVID-19/immunology , COVID-19/virology , Clinical Trials as Topic , Host-Pathogen Interactions/drug effects , Host-Pathogen Interactions/genetics , Host-Pathogen Interactions/immunology , Humans , Neoplasms/genetics , Neoplasms/immunology , Neoplasms/virology , Protein Binding , Receptors, Virus/genetics , Receptors, Virus/metabolism , SARS-CoV-2/drug effects , SARS-CoV-2/immunology , SARS-CoV-2/pathogenicity , Severity of Illness Index , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/metabolism
14.
Signal Transduct Target Ther ; 5(1): 283, 2020 12 04.
Article in English | MEDLINE | ID: covidwho-957563

ABSTRACT

In face of the everlasting battle toward COVID-19 and the rapid evolution of SARS-CoV-2, no specific and effective drugs for treating this disease have been reported until today. Angiotensin-converting enzyme 2 (ACE2), a receptor of SARS-CoV-2, mediates the virus infection by binding to spike protein. Although ACE2 is expressed in the lung, kidney, and intestine, its expressing levels are rather low, especially in the lung. Considering the great infectivity of COVID-19, we speculate that SARS-CoV-2 may depend on other routes to facilitate its infection. Here, we first discover an interaction between host cell receptor CD147 and SARS-CoV-2 spike protein. The loss of CD147 or blocking CD147 in Vero E6 and BEAS-2B cell lines by anti-CD147 antibody, Meplazumab, inhibits SARS-CoV-2 amplification. Expression of human CD147 allows virus entry into non-susceptible BHK-21 cells, which can be neutralized by CD147 extracellular fragment. Viral loads are detectable in the lungs of human CD147 (hCD147) mice infected with SARS-CoV-2, but not in those of virus-infected wild type mice. Interestingly, virions are observed in lymphocytes of lung tissue from a COVID-19 patient. Human T cells with a property of ACE2 natural deficiency can be infected with SARS-CoV-2 pseudovirus in a dose-dependent manner, which is specifically inhibited by Meplazumab. Furthermore, CD147 mediates virus entering host cells by endocytosis. Together, our study reveals a novel virus entry route, CD147-spike protein, which provides an important target for developing specific and effective drug against COVID-19.


Subject(s)
Basigin/genetics , COVID-19/genetics , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/immunology , Animals , Basigin/immunology , COVID-19/immunology , COVID-19/pathology , COVID-19/virology , Host-Pathogen Interactions/immunology , Humans , Lung/immunology , Lung/pathology , Lung/virology , Mice , Pandemics , Protein Binding/immunology , Protein Domains/genetics , Protein Domains/immunology , SARS-CoV-2/pathogenicity , Spike Glycoprotein, Coronavirus/genetics , Virus Internalization
15.
Biochem Biophys Res Commun ; 533(4): 867-871, 2020 12 17.
Article in English | MEDLINE | ID: covidwho-756807

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been discovered as the pathogenic cause of the coronavirus disease 19 (COVID-19). Cellular entry of SARS-CoV-2 are mediated by the spike glycoprotein of virus, and the host specific receptors and proteases. Recently, besides pulmonary complications as the chief symptom, investigations have also revealed that SARS-CoV-2 can trigger neurological manifestations. Herein, to investigate the expression level of receptors and related proteases is important for understanding the neuropathy in COVID-19. We determined the expression levels of receptor ACE2 and CD147, and serine protease TMPRSS2 in human and mouse brain cell lines and mouse different region of brain tissues with qRT-PCR and Western blot. The results showed that the expression pattern of all them was very different to that of lung. ACE2 is lower but CD147 is higher expressed in mostly brain cell lines and mouse brain tissues comparing with lung cell line and tissue, and TMPRSS2 has consistent expression in brain cell lines and mouse lung tissues. It is suggested that SARS-CoV-2 might have a different way of infection to cerebral nervous system. Our finding will offer the clues to predict the possibility of SARS-CoV-2 infection to human brain nervous system and pathogenicity.


Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , Basigin/metabolism , Brain/cytology , Brain/metabolism , Receptors, Coronavirus/metabolism , SARS-CoV-2/metabolism , Serine Endopeptidases/metabolism , Angiotensin-Converting Enzyme 2/genetics , Animals , Basigin/genetics , Cell Line , Humans , Mice , RNA, Messenger/genetics , RNA, Messenger/metabolism , Receptors, Coronavirus/genetics , Serine Endopeptidases/genetics
16.
Genes (Basel) ; 11(9)2020 08 27.
Article in English | MEDLINE | ID: covidwho-738372

ABSTRACT

The recent global COVID-19 public health emergency is caused by SARS-CoV-2 infections and can manifest extremely variable clinical symptoms. Host human genetic variability could influence susceptibility and response to infection. It is known that ACE2 acts as a receptor for this pathogen, but the viral entry into the target cell also depends on other proteins. The aim of this study was to investigate the variability of genes coding for these proteins involved in the SARS-CoV-2 entry into the cells. We analyzed 131 COVID-19 patients by exome sequencing and examined the genetic variants of TMPRSS2, PCSK3, DPP4, and BSG genes. In total we identified seventeen variants. In PCSK3 gene, we observed a missense variant (c.893G>A) statistically more frequent compared to the EUR GnomAD reference population and a missense mutation (c.1906A>G) not found in the GnomAD database. In TMPRSS2 gene, we observed a significant difference in the frequency of c.331G>A, c.23G>T, and c.589G>A variant alleles in COVID-19 patients, compared to the corresponding allelic frequency in GnomAD. Genetic variants in these genes could influence the entry of the SARS-CoV-2. These data also support the hypothesis that host genetic variability may contribute to the variability in infection susceptibility and severity.


Subject(s)
Basigin/genetics , Coronavirus Infections/genetics , Furin/genetics , Mutation , Pneumonia, Viral/genetics , Serine Endopeptidases/genetics , Adolescent , Adult , Aged , Aged, 80 and over , COVID-19 , Child , Child, Preschool , Coronavirus Infections/pathology , Dipeptidyl Peptidase 4/genetics , Exome , Female , Humans , Male , Middle Aged , Pandemics , Pneumonia, Viral/pathology , Polymorphism, Single Nucleotide
17.
Gac Med Mex ; 156(4): 328-333, 2020.
Article in English | MEDLINE | ID: covidwho-732611

ABSTRACT

In the efforts to explain COVID-19 pathophysiology, studies are being carried out on the correspondence between the expression of SARS-CoV-2 cell receptors and viral sequences. ACE2, CD147 and TMPRSS2 receptors expression could indicate poorly explored potential infection targets. For the genomic analysis of SARS-CoV-2 receptors, using BioGPS information was decided, which is a portal that centralizes genetic annotation resources, in combination with that of The Human Protein Atlas, the largest portal of human transcriptome and proteome data. We also reviewed the most recent articles on the subject. RNA and viral receptor proteins expression was observed in numerous anatomical sites, which partially coincides with the information reported in the literature. High expression in testicular cells markedly stood out, and it would be therefore important ruling out whether this anatomical site is a SARS-CoV-2 reservoir; otherwise, germ cell damage, as it is observed in infections with other RNA viruses, should be determined.


En el afán por explicar la fisiopatogenia de COVID-19 se están realizando estudios en torno a la correspondencia entre la expresión de receptores celulares de SARS-CoV-2 y las secuencias virales. La expresión de los receptores ACE2, CD147 y TMPRSS2 podría indicar blancos de infección poco explorados. Para el análisis genómico de los receptores de SARS-CoV-2 se optó por utilizar la información del BioGPS, un portal que centraliza los recursos de anotación genética, en combinación con la de The Human Protein Atlas, el portal más grande de datos del transcriptoma y proteoma humanos. También se revisaron los artículos más recientemente respecto al tema. En numerosos sitios anatómicos se observó la expresión de ARN y proteínas de los receptores del virus, que coinciden parcialmente con la información reportada en la literatura. Resaltó la alta expresión en las células de los testículos, por lo que sería importante descartar si este sitio anatómico es un reservorio de SARS-CoV-2; de no ser así, determinar el daño en las células germinales, tal como sucede en infecciones por otros virus ARN.


Subject(s)
Betacoronavirus/isolation & purification , Coronavirus Infections/virology , Pneumonia, Viral/virology , Testis/virology , Angiotensin-Converting Enzyme 2 , Basigin/genetics , COVID-19 , Coronavirus Infections/physiopathology , Gene Expression Regulation , Humans , Male , Pandemics , Peptidyl-Dipeptidase A/genetics , Pneumonia, Viral/physiopathology , SARS-CoV-2 , Serine Endopeptidases/genetics , Virus Latency
18.
Signal Transduct Target Ther ; 5(1): 121, 2020 07 08.
Article in English | MEDLINE | ID: covidwho-640304
19.
Ocul Immunol Inflamm ; 28(5): 735-738, 2020 Jul 03.
Article in English | MEDLINE | ID: covidwho-616708

ABSTRACT

PURPOSE: The spike proteins of SARS-CoV-2 interact with ACE2 or basigin/CD147 receptors, regulating human-to-human transmissions of COVID-19 together with serine protease TMPRSS2. The expression of these receptors on the ocular surface is unknown. MATERIAL AND METHODS: Gene expression of SARS-CoV-2 receptors was investigated in conjunctival epithelial cell samples and in ex-vivo cornea samples using microarray or transcriptome sequencing. RESULTS: ACE2 is expressed in conjunctival samples at a low level, while BSG and TMPRSS2 are expressed at intermediate levels in both conjunctiva and cornea. Other receptors such as ANPEP, AGTR2 are expressed at low level in the conjunctiva. Two RNA editing enzymes involved in antiviral responses, APOBEC3A, and ADAR-1 were also highly expressed. CONCLUSIONS: The ocular surface may represent an entry point for the SARS-CoV-2 in the human body. The conjunctiva and the cornea can adopt antiviral countermeasures which may explain the low prevalence of eye involvement.


Subject(s)
Betacoronavirus/physiology , Conjunctiva/metabolism , Cornea/metabolism , Coronavirus Infections/metabolism , Gene Expression Regulation/physiology , Pneumonia, Viral/metabolism , Receptors, Virus/genetics , Adenosine Deaminase/genetics , Adolescent , Adult , Aged , Angiotensin-Converting Enzyme 2 , Basigin/genetics , COVID-19 , Child , Cytidine Deaminase/genetics , Gene Expression Profiling , Humans , Middle Aged , Pandemics , Peptidyl-Dipeptidase A/genetics , Proteins/genetics , RNA-Binding Proteins/genetics , SARS-CoV-2 , Serine Endopeptidases/genetics , Young Adult
20.
Allergy ; 75(11): 2829-2845, 2020 11.
Article in English | MEDLINE | ID: covidwho-526792

ABSTRACT

BACKGROUND: Morbidity and mortality from COVID-19 caused by novel coronavirus SARS-CoV-2 is accelerating worldwide, and novel clinical presentations of COVID-19 are often reported. The range of human cells and tissues targeted by SARS-CoV-2, its potential receptors and associated regulating factors are still largely unknown. The aim of our study was to analyze the expression of known and potential SARS-CoV-2 receptors and related molecules in the extensive collection of primary human cells and tissues from healthy subjects of different age and from patients with risk factors and known comorbidities of COVID-19. METHODS: We performed RNA sequencing and explored available RNA-Seq databases to study gene expression and co-expression of ACE2, CD147 (BSG), and CD26 (DPP4) and their direct and indirect molecular partners in primary human bronchial epithelial cells, bronchial and skin biopsies, bronchoalveolar lavage fluid, whole blood, peripheral blood mononuclear cells (PBMCs), monocytes, neutrophils, DCs, NK cells, ILC1, ILC2, ILC3, CD4+ and CD8+ T cells, B cells, and plasmablasts. We analyzed the material from healthy children and adults, and from adults in relation to their disease or COVID-19 risk factor status. RESULTS: ACE2 and TMPRSS2 were coexpressed at the epithelial sites of the lung and skin, whereas CD147 (BSG), cyclophilins (PPIA andPPIB), CD26 (DPP4), and related molecules were expressed in both epithelium and in immune cells. We also observed a distinct age-related expression profile of these genes in the PBMCs and T cells from healthy children and adults. Asthma, COPD, hypertension, smoking, obesity, and male gender status generally led to the higher expression of ACE2- and CD147-related genes in the bronchial biopsy, BAL, or blood. Additionally, CD147-related genes correlated positively with age and BMI. Interestingly, we also observed higher expression of CD147-related genes in the lesional skin of patients with atopic dermatitis. CONCLUSIONS: Our data suggest different receptor repertoire potentially involved in the SARS-CoV-2 infection at the epithelial barriers and in the immune cells. Altered expression of these receptors related to age, gender, obesity and smoking, as well as with the disease status, might contribute to COVID-19 morbidity and severity patterns.


Subject(s)
Angiotensin-Converting Enzyme 2/immunology , Basigin/immunology , COVID-19/epidemiology , Chronic Disease/epidemiology , Dipeptidyl Peptidase 4/immunology , SARS-CoV-2/immunology , Adolescent , Adult , Age Factors , Aged , Angiotensin-Converting Enzyme 2/genetics , Asthma/epidemiology , Asthma/genetics , Asthma/immunology , Basigin/genetics , COVID-19/genetics , COVID-19/immunology , Child , Child, Preschool , Comorbidity , Dipeptidyl Peptidase 4/genetics , Female , Gene Expression/genetics , Humans , Hypertension/epidemiology , Hypertension/genetics , Hypertension/immunology , Immunity, Innate/immunology , Infant , Male , Middle Aged , Obesity/epidemiology , Obesity/genetics , Obesity/immunology , Pulmonary Disease, Chronic Obstructive/epidemiology , Pulmonary Disease, Chronic Obstructive/genetics , Pulmonary Disease, Chronic Obstructive/immunology , Risk Factors , SARS-CoV-2/genetics , Young Adult
SELECTION OF CITATIONS
SEARCH DETAIL