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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
3.
Int J Mol Sci ; 23(5)2022 Feb 25.
Article in English | MEDLINE | ID: covidwho-1736943

ABSTRACT

Rouleaux (stacked clumps) of red blood cells (RBCs) observed in the blood of COVID-19 patients in three studies call attention to the properties of several enveloped virus strains dating back to seminal findings of the 1940s. For COVID-19, key such properties are: (1) SARS-CoV-2 binds to RBCs in vitro and also in the blood of COVID-19 patients; (2) although ACE2 is its target for viral fusion and replication, SARS-CoV-2 initially attaches to sialic acid (SA) terminal moieties on host cell membranes via glycans on its spike protein; (3) certain enveloped viruses express hemagglutinin esterase (HE), an enzyme that releases these glycan-mediated bindings to host cells, which is expressed among betacoronaviruses in the common cold strains but not the virulent strains, SARS-CoV, SARS-CoV-2 and MERS. The arrangement and chemical composition of the glycans at the 22 N-glycosylation sites of SARS-CoV-2 spike protein and those at the sialoglycoprotein coating of RBCs allow exploration of specifics as to how virally induced RBC clumping may form. The in vitro and clinical testing of these possibilities can be sharpened by the incorporation of an existing anti-COVID-19 therapeutic that has been found in silico to competitively bind to multiple glycans on SARS-CoV-2 spike protein.


Subject(s)
COVID-19/metabolism , Erythrocytes/metabolism , SARS-CoV-2/metabolism , Sialoglycoproteins/metabolism , Spike Glycoprotein, Coronavirus/metabolism , Basigin/metabolism , Binding Sites , COVID-19/virology , Glycosylation , Hemagglutination , Hemagglutinins, Viral/metabolism , Humans , N-Acetylneuraminic Acid/metabolism , Polysaccharides/metabolism , Protein Binding , SARS-CoV-2/physiology , Viral Fusion Proteins/metabolism , Virus Internalization
4.
Respiration ; 101(6): 610-618, 2022.
Article in English | MEDLINE | ID: covidwho-1626135

ABSTRACT

BACKGROUND: The novel beta-coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), enters the human body via mucosal surfaces of the upper and/or lower respiratory tract. Viral entry into epithelial cells is mediated via angiotensin-converting enzyme 2 (ACE2) and auxiliary molecules, but the precise anatomic site of infection still remains unclear. METHODS: Here, we systematically investigated the main SARS-CoV-2 receptor proteins ACE2 and transmembrane serine protease 2 (TMPRSS2), as well as 2 molecules potentially involved in viral entry, furin and CD147, in formalin-fixed, paraffin-embedded human tissues. Tissue microarrays incorporating a total of 879 tissue cores from conjunctival (n = 84), sinonasal (n = 95), and lung (bronchiolar/alveolar; n = 96) specimens were investigated for protein expression by immunohistochemistry. RESULTS: ACE2 and TMPRSS2 were expressed in ciliated epithelial cells of the conjunctivae and sinonasal tissues, with highest expression levels observed in the apical cilia. In contrast, in the lung, the expression of those molecules in bronchiolar and alveolar epithelial cells was much rarer and only very focal when present. Furin and CD147 were more uniformly expressed in all tissues analyzed, including the lung. Interestingly, alveolar macrophages consistently expressed high levels of all 4 molecules investigated. CONCLUSIONS: Our study confirms and extends previous findings and contributes to a better understanding of potential SARS-CoV-2 infection sites along the human respiratory tract.


Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , Basigin/metabolism , Furin/metabolism , Respiratory System/metabolism , SARS-CoV-2 , Serine Endopeptidases/metabolism , Virus Internalization , COVID-19/metabolism , COVID-19/virology , Humans , Lung/metabolism , Respiratory System/virology
5.
Clin Sci (Lond) ; 135(24): 2667-2689, 2021 12 22.
Article in English | MEDLINE | ID: covidwho-1585742

ABSTRACT

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes a broad range of clinical responses including prominent microvascular damage. The capacity of SARS-CoV-2 to infect vascular cells is still debated. Additionally, the SARS-CoV-2 Spike (S) protein may act as a ligand to induce non-infective cellular stress. We tested this hypothesis in pericytes (PCs), which are reportedly reduced in the heart of patients with severe coronavirus disease-2019 (COVID-19). Here we newly show that the in vitro exposure of primary human cardiac PCs to the SARS-CoV-2 wildtype strain or the α and δ variants caused rare infection events. Exposure to the recombinant S protein alone elicited signalling and functional alterations, including: (1) increased migration, (2) reduced ability to support endothelial cell (EC) network formation on Matrigel, (3) secretion of pro-inflammatory molecules typically involved in the cytokine storm, and (4) production of pro-apoptotic factors causing EC death. Next, adopting a blocking strategy against the S protein receptors angiotensin-converting enzyme 2 (ACE2) and CD147, we discovered that the S protein stimulates the phosphorylation/activation of the extracellular signal-regulated kinase 1/2 (ERK1/2) through the CD147 receptor, but not ACE2, in PCs. The neutralisation of CD147, either using a blocking antibody or mRNA silencing, reduced ERK1/2 activation, and rescued PC function in the presence of the S protein. Immunoreactive S protein was detected in the peripheral blood of infected patients. In conclusion, our findings suggest that the S protein may prompt PC dysfunction, potentially contributing to microvascular injury. This mechanism may have clinical and therapeutic implications.


Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , Basigin/metabolism , Myocardium/enzymology , Pericytes/enzymology , SARS-CoV-2/physiology , Spike Glycoprotein, Coronavirus/blood , Adolescent , Adult , Aged , Aged, 80 and over , COVID-19/blood , Caco-2 Cells , Cell Death , Child , Child, Preschool , Cytokines/metabolism , Female , Host-Pathogen Interactions , Humans , Infant , Infant, Newborn , Male , Middle Aged , Myocardium/cytology , Pericytes/virology , Primary Cell Culture , Young Adult
6.
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
7.
Clin Sci (Lond) ; 135(24): 2667-2689, 2021 12 22.
Article in English | MEDLINE | ID: covidwho-1528037

ABSTRACT

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes a broad range of clinical responses including prominent microvascular damage. The capacity of SARS-CoV-2 to infect vascular cells is still debated. Additionally, the SARS-CoV-2 Spike (S) protein may act as a ligand to induce non-infective cellular stress. We tested this hypothesis in pericytes (PCs), which are reportedly reduced in the heart of patients with severe coronavirus disease-2019 (COVID-19). Here we newly show that the in vitro exposure of primary human cardiac PCs to the SARS-CoV-2 wildtype strain or the α and δ variants caused rare infection events. Exposure to the recombinant S protein alone elicited signalling and functional alterations, including: (1) increased migration, (2) reduced ability to support endothelial cell (EC) network formation on Matrigel, (3) secretion of pro-inflammatory molecules typically involved in the cytokine storm, and (4) production of pro-apoptotic factors causing EC death. Next, adopting a blocking strategy against the S protein receptors angiotensin-converting enzyme 2 (ACE2) and CD147, we discovered that the S protein stimulates the phosphorylation/activation of the extracellular signal-regulated kinase 1/2 (ERK1/2) through the CD147 receptor, but not ACE2, in PCs. The neutralisation of CD147, either using a blocking antibody or mRNA silencing, reduced ERK1/2 activation, and rescued PC function in the presence of the S protein. Immunoreactive S protein was detected in the peripheral blood of infected patients. In conclusion, our findings suggest that the S protein may prompt PC dysfunction, potentially contributing to microvascular injury. This mechanism may have clinical and therapeutic implications.


Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , Basigin/metabolism , Myocardium/enzymology , Pericytes/enzymology , SARS-CoV-2/physiology , Spike Glycoprotein, Coronavirus/blood , Adolescent , Adult , Aged , Aged, 80 and over , COVID-19/blood , Caco-2 Cells , Cell Death , Child , Child, Preschool , Cytokines/metabolism , Female , Host-Pathogen Interactions , Humans , Infant , Infant, Newborn , Male , Middle Aged , Myocardium/cytology , Pericytes/virology , Primary Cell Culture , Young Adult
8.
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
9.
Virulence ; 12(1): 2214-2227, 2021 12.
Article in English | MEDLINE | ID: covidwho-1398027

ABSTRACT

An oral antiviral against SARS-CoV-2 that also attenuates inflammatory instigators of severe COVID-19 is not available to date. Herein, we show that the apoA-I mimetic peptide 4 F inhibits Spike mediated viral entry and has antiviral activity against SARS-CoV-2 in human lung epithelial Calu3 and Vero-E6 cells. In SARS-CoV-2 infected Calu3 cells, 4 F upregulated inducers of the interferon pathway such as MX-1 and Heme oxygenase 1 (HO-1) and downregulated mitochondrial reactive oxygen species (mito-ROS) and CD147, a host protein that mediates viral entry. 4 F also reduced associated cellular apoptosis and secretion of IL-6 in both SARS-CoV-2 infected Vero-E6 and Calu3 cells. Thus, 4 F attenuates in vitro SARS-CoV-2 replication, associated apoptosis in epithelial cells and secretion of IL-6, a major cytokine related to COVID-19 morbidity. Given established safety of 4 F in humans, clinical studies are warranted to establish 4 F as therapy for COVID-19.


Subject(s)
Antiviral Agents/pharmacology , Peptides/pharmacology , SARS-CoV-2/drug effects , Virus Replication/drug effects , Animals , Antioxidants/pharmacology , Apoptosis/drug effects , Basigin/metabolism , Cytokines/metabolism , Epithelial Cells , Heparan Sulfate Proteoglycans/metabolism , Humans , Inflammation , Interferons/metabolism , Oxidative Stress/drug effects , SARS-CoV-2/physiology , Spike Glycoprotein, Coronavirus/metabolism , Virus Attachment/drug effects , Virus Internalization/drug effects
11.
J Assist Reprod Genet ; 37(11): 2657-2660, 2020 Nov.
Article in English | MEDLINE | ID: covidwho-1384515

ABSTRACT

PURPOSE: To visualize SARS-CoV-2 host receptors ACE2 and CD147 on human oocytes and blastocysts. METHODS: Immunohistochemistry and confocal microscopy on human primary oocytes and pre (5 days post fertilization (dpf5) and (dpf6))- and peri (dpf7)-implantation blastocysts donated to research. RESULTS: SARS-CoV-2 host receptors ACE2 and CD147 are present on the membrane of trophectoderm, epiblast and hypoblast cells in human blastocysts. CD147 is also present on the oolemma. CONCLUSION: Theoretically, the earliest stages of embryonic development may be vulnerable for SARS-CoV-2 infection.


Subject(s)
Basigin/metabolism , Blastocyst/metabolism , Oocytes/metabolism , Peptidyl-Dipeptidase A/metabolism , Angiotensin-Converting Enzyme 2 , Female , Humans , Immunohistochemistry
12.
mSphere ; 6(4): e0064721, 2021 08 25.
Article in English | MEDLINE | ID: covidwho-1352536

ABSTRACT

Basigin, or CD147, has been reported as a coreceptor used by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) to invade host cells. Basigin also has a well-established role in Plasmodium falciparum malaria infection of human erythrocytes, where it is bound by one of the parasite's invasion ligands, reticulocyte binding protein homolog 5 (RH5). Here, we sought to validate the claim that the receptor binding domain (RBD) of SARS-CoV-2 spike glycoprotein can form a complex with basigin, using RH5-basigin as a positive control. Using recombinantly expressed proteins, size exclusion chromatography and surface plasmon resonance, we show that neither RBD nor full-length spike glycoprotein bind to recombinant human basigin (expressed in either Escherichia coli or mammalian cells). Further, polyclonal anti-basigin IgG did not block SARS-CoV-2 infection of Vero E6 cells. Given the immense interest in SARS-CoV-2 therapeutic targets to improve treatment options for those who become seriously ill with coronavirus disease 2019 (COVID-19), we would caution the inclusion of basigin in this list on the basis of its reported direct interaction with SARS-CoV-2 spike glycoprotein. IMPORTANCE Reducing the mortality and morbidity associated with COVID-19 remains a global health priority. Vaccines have proven highly effective at preventing infection and hospitalization, but efforts must continue to improve treatment options for those who still become seriously ill. Critical to these efforts is the identification of host factors that are essential to viral entry and replication. Basigin, or CD147, was previously identified as a possible therapeutic target based on the observation that it may act as a coreceptor for SARS-CoV-2, binding to the receptor binding domain of the spike protein. Here, we show that there is no direct interaction between the RBD and basigin, casting doubt on its role as a coreceptor and plausibility as a therapeutic target.


Subject(s)
Basigin/metabolism , COVID-19/metabolism , COVID-19/virology , SARS-CoV-2/metabolism , Spike Glycoprotein, Coronavirus/metabolism , Animals , Basigin/immunology , COVID-19/immunology , Cell Line , Chlorocebus aethiops , Host-Pathogen Interactions/immunology , Humans , Protein Binding/immunology , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/immunology , Vero Cells , Virus Internalization
13.
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
14.
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
15.
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
16.
Stem Cell Res ; 51: 102200, 2021 03.
Article in English | MEDLINE | ID: covidwho-1051937

ABSTRACT

Recently, coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 has spread around the world and is receiving worldwide attention. Approximately 20% of infected patients are suffering from severe disease of multiple systems and in danger of death, while the ocular complications of SARS-CoV-2-infected patients have not been reported generally. Herein, we focus on two major receptors of SARS-CoV-2, ACE2 and CD147 (BSG), in human ocular cells, and interpret the potential roles of coronaviruses in human ocular tissues and diseases.


Subject(s)
COVID-19/pathology , Eye/virology , Angiotensin-Converting Enzyme 2/chemistry , Angiotensin-Converting Enzyme 2/metabolism , Animals , Antirheumatic Agents/therapeutic use , Basigin/metabolism , COVID-19/drug therapy , COVID-19/transmission , COVID-19/virology , Dexamethasone/therapeutic use , Eye/cytology , Eye/metabolism , Eye Diseases/pathology , Eye Diseases/virology , Glucocorticoids/therapeutic use , Humans , Renin-Angiotensin System/physiology , SARS-CoV-2/isolation & purification
17.
Sci Rep ; 11(1): 413, 2021 01 11.
Article in English | MEDLINE | ID: covidwho-1019887

ABSTRACT

The spike protein of SARS-CoV-2 is known to enable viral invasion into human cells through direct binding to host receptors including ACE2. An alternate entry receptor for the virus was recently proposed to be basigin/CD147. These early studies have already prompted a clinical trial and multiple published hypotheses speculating on the role of this host receptor in viral infection and pathogenesis. Here, we report that we are unable to find evidence supporting the role of basigin as a putative spike binding receptor. Recombinant forms of the SARS-CoV-2 spike do not interact with basigin expressed on the surface of human cells, and by using specialized assays tailored to detect receptor interactions as weak or weaker than the proposed basigin-spike binding, we report no evidence for a direct interaction between the viral spike protein to either of the two common isoforms of basigin. Finally, removing basigin from the surface of human lung epithelial cells by CRISPR/Cas9 results in no change in their susceptibility to SARS-CoV-2 infection. Given the pressing need for clarity on which viral targets may lead to promising therapeutics, we present these findings to allow more informed decisions about the translational relevance of this putative mechanism in the race to understand and treat COVID-19.


Subject(s)
Basigin/metabolism , COVID-19/metabolism , Receptors, Virus/metabolism , SARS-CoV-2/physiology , Spike Glycoprotein, Coronavirus/metabolism , COVID-19/virology , Cell Line , HEK293 Cells , Host-Pathogen Interactions , Humans , Protein Binding , Virus Internalization
19.
J Proteome Res ; 20(1): 49-59, 2021 01 01.
Article in English | MEDLINE | ID: covidwho-989659

ABSTRACT

Since the novel coronavirus pandemic, people around the world have been touched in varying degrees, and this pandemic has raised a major global health concern. As there is no effective drug or vaccine, it is urgent to find therapeutic drugs that can serve to deal with the current epidemic situation in all countries and regions. We searched drugs and response measures for SARS-CoV-2 in the PubMed database, and then updated the potential targets and therapeutic drugs from the perspective of the viral replication cycle. The drug research studies of the viral replication cycle are predominantly focused on the process of the virus entering cells, proteases, and RdRp. The inhibitors of the virus entry to cells and RdRp, such as Arbidol, remdesivir, favipiravir, EIDD-2081, and ribavirin, are in clinical trials, while most of the protease inhibitors are mainly calculated by molecular docking technology, which needs in vivo and in vitro experiments to prove the effect for SARS-CoV-2. This review summarizes the drugs targeting the viral replication process and provides a basis and directions for future drug development and reuse on the protein level of COVID-19.


Subject(s)
Antiviral Agents/pharmacology , SARS-CoV-2/drug effects , Virus Replication/drug effects , Angiotensin-Converting Enzyme 2/metabolism , Animals , Antiviral Agents/chemistry , Basigin/metabolism , Coronavirus 3C Proteases/antagonists & inhibitors , Coronavirus 3C Proteases/metabolism , Coronavirus Nucleocapsid Proteins/chemistry , Coronavirus Nucleocapsid Proteins/metabolism , Coronavirus RNA-Dependent RNA Polymerase/metabolism , Dipeptidyl Peptidase 4/metabolism , Furin/antagonists & inhibitors , Furin/metabolism , Host-Pathogen Interactions/drug effects , Humans , SARS-CoV-2/pathogenicity , SARS-CoV-2/physiology , Serine Endopeptidases/metabolism , Small Molecule Libraries/pharmacology , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/metabolism
20.
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
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