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1.
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
3.
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
5.
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
6.
Mol Biol Rep ; 47(10): 8229-8233, 2020 Oct.
Article in English | MEDLINE | ID: covidwho-754391

ABSTRACT

COVID-19 caused by the SARS-CoV-2 outbreak quickly has turned into a pandemic. However, no specific antiviral agent is yet available. In this communication, we aimed to evaluate the significance of CD147 protein and the potential protective effect of melatonin that is mediated by this protein in COVID-19. CD147 is a glycoprotein that is responsible for the cytokine storm in the lungs through the mediation of viral invasion. Melatonin use previously was shown to reduce cardiac damage by blocking the CD147 activity. Hence, melatonin, a safe drug, may prevent severe symptoms, reduce symptom severity and the adverse effects of the other antiviral drugs in COVID-19 patients. In conclusion, the use of melatonin, which is reduced in the elderly and immune-compromised patients, should be considered as an adjuvant through its CD147 suppressor and immunomodulatory effect.


Subject(s)
Adjuvants, Pharmaceutic/therapeutic use , Antiviral Agents/therapeutic use , Basigin/metabolism , Coronavirus Infections/drug therapy , Melatonin/therapeutic use , Pneumonia, Viral/drug therapy , Animals , Antioxidants/metabolism , Antiviral Agents/pharmacology , Basigin/antagonists & inhibitors , COVID-19 , Coronavirus Infections/metabolism , Humans , Immune System/drug effects , Melatonin/pharmacology , Pandemics , Pneumonia, Viral/metabolism , Signal Transduction/drug effects
7.
Stem Cell Rev Rep ; 16(3): 434-440, 2020 06.
Article in English | MEDLINE | ID: covidwho-71853

ABSTRACT

The expressive number of deaths and confirmed cases of SARS-CoV-2 call for an urgent demand of effective and available drugs for COVID-19 treatment. CD147, a receptor on host cells, is a novel route for SARS-CoV-2 invasion. Thus, drugs that interfere in the spike protein/CD147 interaction or CD147 expression may inhibit viral invasion and dissemination among other cells, including in progenitor/stem cells. Studies suggest beneficial effects of azithromycin in reducing viral load of hospitalized patients, possibly interfering with ligand/CD147 receptor interactions; however, its possible effects on SARS-CoV-2 invasion has not yet been evaluated. In addition to the possible effect in invasion, azithromycin decreases the expression of some metalloproteinases (downstream to CD147), induces anti-viral responses in primary human bronchial epithelial infected with rhinovirus, decreasing viral replication and release. Moreover, resident lung progenitor/stem are extensively differentiated into myofibroblasts during pulmonary fibrosis, a complication observed in COVID-19 patients. This process, and the possible direct viral invasion of progenitor/stem cells via CD147 or ACE2, could result in the decline of these cellular stocks and failing lung repair. Clinical tests with allogeneic MSCs from healthy individuals are underway to enhance endogenous lung repair and suppress inflammation.


Subject(s)
Anti-Bacterial Agents/therapeutic use , Azithromycin/therapeutic use , Basigin/genetics , Betacoronavirus/drug effects , Coronavirus Infections/therapy , Pandemics , Pneumonia, Viral/therapy , Spike Glycoprotein, Coronavirus/genetics , Stem Cell Transplantation , Angiotensin-Converting Enzyme 2 , B-Lymphocytes/drug effects , B-Lymphocytes/immunology , B-Lymphocytes/virology , Basigin/antagonists & inhibitors , Basigin/immunology , Betacoronavirus/metabolism , Betacoronavirus/pathogenicity , COVID-19 , Clinical Trials as Topic , Coronavirus Infections/epidemiology , Coronavirus Infections/immunology , Coronavirus Infections/virology , Gene Expression , Host-Pathogen Interactions/drug effects , Host-Pathogen Interactions/immunology , Humans , Lung/immunology , Lung/virology , Peptidyl-Dipeptidase A/genetics , Peptidyl-Dipeptidase A/immunology , Pneumonia, Viral/epidemiology , Pneumonia, Viral/immunology , Pneumonia, Viral/virology , Protein Binding/drug effects , SARS-CoV-2 , Spike Glycoprotein, Coronavirus/antagonists & inhibitors , Spike Glycoprotein, Coronavirus/immunology , Stem Cells/drug effects , Stem Cells/immunology , Stem Cells/virology , T-Lymphocytes/drug effects , T-Lymphocytes/immunology , T-Lymphocytes/virology , Viral Load/drug effects
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