scholarly journals Cholesterol-Rich Lipid Rafts as Platforms for SARS-CoV-2 Entry

2021 ◽  
Vol 12 ◽  
Author(s):  
Selvin Noé Palacios-Rápalo ◽  
Luis Adrián De Jesús-González ◽  
Carlos Daniel Cordero-Rivera ◽  
Carlos Noe Farfan-Morales ◽  
Juan Fidel Osuna-Ramos ◽  
...  
Keyword(s):  
Lipid Rafts ◽  
Serine Proteases ◽  
Scavenger Receptor ◽  
Membrane Microdomains ◽  
The Novel ◽  
Angiotensin Converting Enzyme 2 ◽  
Host Interactions ◽  
Functional Membrane ◽  
Approved Drugs

Since its appearance, the Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV-2), the causal agent of Coronavirus Disease 2019 (COVID-19), represents a global problem for human health that involves the host lipid homeostasis. Regarding, lipid rafts are functional membrane microdomains with highly and tightly packed lipid molecules. These regions enriched in sphingolipids and cholesterol recruit and concentrate several receptors and molecules involved in pathogen recognition and cellular signaling. Cholesterol-rich lipid rafts have multiple functions for viral replication; however, their role in SARS-CoV-2 infection remains unclear. In this review, we discussed the novel evidence on the cholesterol-rich lipid rafts as a platform for SARS-CoV-2 entry, where receptors such as the angiotensin-converting enzyme-2 (ACE-2), heparan sulfate proteoglycans (HSPGs), human Toll-like receptors (TLRs), transmembrane serine proteases (TMPRSS), CD-147 and HDL-scavenger receptor B type 1 (SR-B1) are recruited for their interaction with the viral spike protein. FDA-approved drugs such as statins, metformin, hydroxychloroquine, and cyclodextrins (methyl-β-cyclodextrin) can disrupt cholesterol-rich lipid rafts to regulate key molecules in the immune signaling pathways triggered by SARS-CoV-2 infection. Taken together, better knowledge on cholesterol-rich lipid rafts in the SARS-CoV-2-host interactions will provide valuable insights into pathogenesis and the identification of novel therapeutic targets.

scholarly journals Antibodies from a Patient with Type 1 Diabetes and Celiac Disease Bind to Macrophages that Express the Scavenger Receptor CD163

2011 ◽  
Vol 25 (6) ◽  
pp. 327-329 ◽  
Author(s):  
Brigitte Sonier ◽  
Alexander Strom ◽  
Gen-Sheng Wang ◽  
Christopher Patrick ◽  
Jennifer A Crookshank ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Celiac Disease ◽  
Molecular Mimicry ◽  
Scavenger Receptor ◽  
Cross Reactivity ◽  
Rat Jejunum ◽  
The Novel ◽  
Blood Monocytes ◽  
Specific Subset

Antibodies against the wheat storage globulin Glo-3A from a patient with both type 1 diabetes (T1D) and celiac disease were enriched to identify potential molecular mimicry between wheat antigens and T1D target tissues. Recombinant Glo-3A was used to enrich anti-Glo-3A immunoglobulin G antibodies from plasma by batch affinity chromatography. Rat jejunum and pancreas, as well as human duodenum and monocytes were probed, and binding was evaluated by immunohistochemistry and confocal microscopy. Glo-3A-enriched antibodies bound to a specific subset of cells in the lamina propria of rat jejunum that co-localized mostly with a marker of resident, alternatively activated CD163-positive (CD163+) macrophages. Blood monocytes and macrophage-like cells in human duodenum were also labelled with the enriched antibodies. Blocking studies revealed that binding to CD163+macrophages was not due to cross-reactivity with anti-Glo-3A antibodies, but rather to non-Glo-3A antibodies co-purified during antibody enrichment. The novel finding of putative autoantibodies against tolerogenic intestinal CD163+macrophages suggests that regulatory macrophages were targeted in this patient with celiac disease and T1D.

scholarly journals Targeting Lipid Rafts as a Strategy Against Coronavirus

2021 ◽  
Vol 8 ◽  
Author(s):  
Maurizio Sorice ◽  
Roberta Misasi ◽  
Gloria Riitano ◽  
Valeria Manganelli ◽  
Stefano Martellucci ◽  
...  
Keyword(s):  
Host Cell ◽  
Lipid Rafts ◽  
Viral Envelope ◽  
Host Cells ◽  
Spike Protein ◽  
Membrane Microdomains ◽  
Virus Infectivity ◽  
Necrosis Factor Alpha ◽  
Functional Membrane ◽  
Host Cell Membranes

Lipid rafts are functional membrane microdomains containing sphingolipids, including gangliosides, and cholesterol. These regions are characterized by highly ordered and tightly packed lipid molecules. Several studies revealed that lipid rafts are involved in life cycle of different viruses, including coronaviruses. Among these recently emerged the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). The main receptor for SARS-CoV-2 is represented by the angiotensin-converting enzyme-2 (ACE-2), although it also binds to sialic acids linked to host cell surface gangliosides. A new type of ganglioside-binding domain within the N-terminal portion of the SARS-CoV-2 spike protein was identified. Lipid rafts provide a suitable platform able to concentrate ACE-2 receptor on host cell membranes where they may interact with the spike protein on viral envelope. This review is focused on selective targeting lipid rafts components as a strategy against coronavirus. Indeed, cholesterol-binding agents, including statins or methyl-β-cyclodextrin (MβCD), can affect cholesterol, causing disruption of lipid rafts, consequently impairing coronavirus adhesion and binding. Moreover, these compounds can block downstream key molecules in virus infectivity, reducing the levels of proinflammatory molecules [tumor necrosis factor alpha (TNF-α), interleukin (IL)-6], and/or affecting the autophagic process involved in both viral replication and clearance. Furthermore, cyclodextrins can assemble into complexes with various drugs to form host–guest inclusions and may be used as pharmaceutical excipients of antiviral compounds, such as lopinavir and remdesivir, by improving bioavailability and solubility. In conclusion, the role of lipid rafts-affecting drugs in the process of coronavirus entry into the host cells prompts to introduce a new potential task in the pharmacological approach against coronavirus.

Possible therapeutic interventions in COVID-19 induced ARDS by cotinine as an ACE-2 promoter and AT-1R blocker

2020 ◽  
Vol 20 ◽  
Author(s):  
Tarun Sharma ◽  
Sidharth Mehan
Keyword(s):  
Protein Binding ◽  
Plasma Protein Binding ◽  
Plasma Protein ◽  
Distress Syndrome ◽  
Therapeutic Interventions ◽  
Promising Candidate ◽  
Angiotensin Converting Enzyme 2 ◽  
Proinflammatory Effect ◽  
Pulmonary Permeability

: In these challenging times of the pandemic, as coronavirus disease 2019 (COVID-19) has taken over the planet, its complications such as acute respiratory distress syndrome (ARDS) have the potential to wipe out a large portion of our population. Whereas a serious lack of ventilators, vaccine being months away makes the condition even worse. That's why promising drug therapy is required. One of them was suggested in this article. It is the angiotensin-converting enzyme-2 (ACE-2) to which the COVID-19 virus binds and upon downregulation of which the pulmonary permeability increases and results in the filling of alveoli by proteinaceous fluids, which finally results in ARDS. ARDS can be assisted by angiotensinII type-1 receptor (AT-1R) blocker and ACE-2 upregulator. AT-1R blocker will prevent vasoconstriction, the proinflammatory effect seen otherwise upon its activation. ACE-2 upregulation will ensure less formation of angiotensin II, vasodilatory effects due to the formation of angiotensin (1-7), increased breakdown of bradykinin at lung level. Overall, decreased vasoconstriction of vessels supplying lungs and decreased vasodilation of lung tissues will ensure decreased pulmonary permeability and eventually relieve ARDS. It should also be considered that all components of the reninangiotensin-aldosterone system (RAAS) are located in the lung tissues. A drug with the least plasma protein binding is required to ensure its distribution across these lung tissues. Cotinine appears to be a promising candidate for COVID-19- induced ARDS. It acts across the board and acts as both an AT-1R blocker, ACE-2 upregulator. It also has a weak plasma protein binding that helps to spread through the lung tissues. In this review, we summarized that cotinine, along with COVID-19 virus replication blocker anti-virals, may prove to be a promising therapy for the treatment of COVID-19 induced ARDS.

The Free Responsible Action of the Individual

2018 ◽  
Author(s):  
Michael P. DeJonge
Keyword(s):  
The Novel ◽  
Extreme Situation ◽  
The Third ◽  
Third Phase ◽  
Responsible Action ◽  
Action Type ◽  
Two Phases ◽  
The Individual ◽  
The Church

If, as Chapter 12 argues, much of Bonhoeffer’s resistance thinking remains stable even as he undertakes the novel conspiratorial resistance, what is new in his resistance thinking in the third phase? What receives new theological elaboration is the resistance activity of the individual, which in the first two phases was overshadowed by the resistance role played by the church. Indeed, as this chapter shows, Bonhoeffer’s conspiratorial activity is associated with what he calls free responsible action (type 6), and this is the action of the individual, not the church, in the exercise of vocation. As such, the conspiratorial activity is most closely related to the previously developed type 1 resistance, which includes individual vocational action in response to state injustice. But the conspiratorial activity differs from type 1 resistance as individual vocational action in the extreme situation.

575 Regression by hetIL-15 monotherapy in different mouse breast cancer models correlates with intratumoral infiltration of a novel population of dendritic cells

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A609-A609
Author(s):  
Sevasti Karaliota ◽  
Dimitris Stellas ◽  
Vasiliki Stravokefalou ◽  
Bethany Nagy ◽  
Cristina Bergamaschi ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Dendritic Cells ◽  
Nk Cells ◽  
Flow Analysis ◽  
Laboratory Animals ◽  
Tumor Infiltration ◽  
The Novel ◽  
Phenotypic Profile ◽  
Conventional Type

BackgroundIL-15 is a cytokine which stimulates the proliferation and cytotoxic function of CD8+ T and NK cells. We have produced and applied the native heterodimeric IL-15 (hetIL-15) on several preclinical models, which have supported the anti-tumor activity of hetIL-15. Based on these results, hetIL-15 has advanced to clinical trials. The objectives of this study were to explore how hetIL-15 shapes the tumor microenviroment and to characterize the interactions between tumor-infiltrating lymphoid and myeloid cells.MethodsWe studied the efficacy of locoregional administration of heterodimeric IL-15 (hetIL-15) in two different orthotopic triple-negative breast cancer (TNBC) mouse models, syngeneic for C57BL/6 and Balb/c, respectively. The effects of hetIL-15 on immune cells were analyzed by flow cytometry, immunohistochemistry (IHC) and gene expression profiling. The profile of the novel infiltrated dendritic cell populations was further explored by bulk and single cell RNAseq.Results hetIL-15 resulted in tumor eradication in 40% of treated mice and reduction of metastasis. Subsequent rechallenges with the same cell line failed to generate tumor regrowth, suggesting the development of immunological memory in hetIL-15 treated mice. hetIL-15 promoted tumor accumulation of proliferating and cytotoxic CD8+ T and NK cells. Additionally, peritumoral hetIL-15 administration resulted in an increased tumor infiltration of both conventional type 1 dendritic cells (cDC1s) and of a novel DC population found only in the hetIL-15 treated animals. Phenotypic profile analysis confirmed the expression of several cDC1 specific markers, including CD103 and IRF8 on this DC population.Transcriptomics and flow analysis of intratumoral dendritic cells indicate that the new hetIL-15 induced cells reside preferentially in the tumors and are distinct from cDC1 and cDC2 populations. Both cDC1s and the novel DC population were inversely correlated with the tumor size.ConclusionsLocoregional administration of hetIL-15 results in complete eradication of EO771 and significant reduction of 4T1 primary breast cancer tumors, prolonged survival and long-lasting specific anti-tumor immunity. hetIL-15 increases the tumor infiltration of activated T and NK cells and intensifies the tumor infiltration of conventional type 1 dendritic cells (cDC1) and a new population of dendritic cells. We propose that the anti-cancer activity of hetIL-15 in primary EO771 tumors is orchestrated by the interplay of NK, CD8+T cells, cDC1 and a novel subset of DCs with a distinct phenotypic profile. These findings suggest a role for hetIL-15 in the treatment of breast cancer.Ethics ApprovalThe study was approved by the National Cancer Institute-Frederick Animal Care and Use Committee, approval number 19–324 and was conducted in accordance with the ACUC guidelines and the NIH Guide for the Care and Use of Laboratory Animals.

scholarly journals SARS-CoV-2 Entry: At the Crossroads of CD147 and ACE2

Cells ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 1434
Author(s):  
Claudio Fenizia ◽  
Silvia Galbiati ◽  
Claudia Vanetti ◽  
Riccardo Vago ◽  
Mario Clerici ◽  
...  
Keyword(s):  
Underlying Mechanism ◽  
Membrane Receptors ◽  
Host Cells ◽  
Viral Agent ◽  
Blocking Antibody ◽  
Angiotensin Converting Enzyme 2 ◽  
Host Membrane ◽  
B Virus ◽  
Immunodeficiency Virus

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.

scholarly journals Electron Paramagnetic Resonance Gives Evidence for the Presence of Type 1 Gonadotropin-Releasing Hormone Receptor (GnRH-R) in Subdomains of Lipid Rafts

Molecules ◽  
2021 ◽  
Vol 26 (4) ◽  
pp. 973
Author(s):  
Tilen Koklič ◽  
Alenka Hrovat ◽  
Ramon Guixà-González ◽  
Ismael Rodríguez-Espigares ◽  
Damaris Navio ◽  
...  
Keyword(s):  
Lipid Rafts ◽  
Order Parameter ◽  
Spin Probe ◽  
Gonadotropin Releasing Hormone ◽  
Paramagnetic Resonance ◽  
Hek 293 ◽  
293 Cells ◽  
Gonadotropin Releasing Hormone Receptor ◽  
Electron Paramagnetic

This study investigated the effect of type 1 gonadotropin releasing hormone receptor (GnRH-R) localization within lipid rafts on the properties of plasma membrane (PM) nanodomain structure. Confocal microscopy revealed colocalization of PM-localized GnRH-R with GM1-enriched raft-like PM subdomains. Electron paramagnetic resonance spectroscopy (EPR) of a membrane-partitioned spin probe was then used to study PM fluidity of immortalized pituitary gonadotrope cell line αT3-1 and HEK-293 cells stably expressing GnRH-R and compared it with their corresponding controls (αT4 and HEK-293 cells). Computer-assisted interpretation of EPR spectra revealed three modes of spin probe movement reflecting the properties of three types of PM nanodomains. Domains with an intermediate order parameter (domain 2) were the most affected by the presence of the GnRH-Rs, which increased PM ordering (order parameter (S)) and rotational mobility of PM lipids (decreased rotational correlation time (τc)). Depletion of cholesterol by methyl-β-cyclodextrin (methyl-β-CD) inhibited agonist-induced GnRH-R internalization and intracellular Ca2+ activity and resulted in an overall reduction in PM order; an observation further supported by molecular dynamics (MD) simulations of model membrane systems. This study provides evidence that GnRH-R PM localization may be related to a subdomain of lipid rafts that has lower PM ordering, suggesting lateral heterogeneity within lipid raft domains.

scholarly journals Blocking Effect of Demethylzeylasteral on the Interaction between Human ACE2 Protein and SARS-CoV-2 RBD Protein Discovered Using SPR Technology

Molecules ◽  
2020 ◽  
Vol 26 (1) ◽  
pp. 57
Author(s):  
Zhi-Ling Zhu ◽  
Xiao-Dan Qiu ◽  
Shuo Wu ◽  
Yi-Tong Liu ◽  
Ting Zhao ◽  
...  
Keyword(s):  
Therapeutic Strategy ◽  
Blocking Effect ◽  
Spike Protein ◽  
Binding Affinities ◽  
The Novel ◽  
Converting Enzyme ◽  
Primary Method ◽  
Angiotensin Converting Enzyme 2 ◽  
Novel Coronavirus ◽  
Effective Drugs

The novel coronavirus disease (2019-nCoV) has been affecting global health since the end of 2019, and there is no sign that the epidemic is abating. Targeting the interaction between the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein and the human angiotensin-converting enzyme 2 (ACE2) receptor is a promising therapeutic strategy. In this study, surface plasmon resonance (SPR) was used as the primary method to screen a library of 960 compounds. A compound 02B05 (demethylzeylasteral, CAS number: 107316-88-1) that had high affinities for S-RBD and ACE2 was discovered, and binding affinities (KD, μM) of 02B05-ACE2 and 02B05-S-RBD were 1.736 and 1.039 μM, respectively. The results of a competition experiment showed that 02B05 could effectively block the binding of S-RBD to ACE2 protein. Furthermore, pseudovirus infection assay revealed that 02B05 could inhibit entry of SARS-CoV-2 pseudovirus into 293T cells to a certain extent at nontoxic concentration. The compoundobtained in this study serve as references for the design of drugs which have potential in the treatment of COVID-19 and can thus accelerate the process of developing effective drugs to treat SARS-CoV-2 infections.

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