scholarly journals Peptide Derivatives of Platelet-Derived Growth Factor Receptor Alpha Inhibit Cell-Associated Spread of Human Cytomegalovirus

Viruses ◽  
2021 ◽  
Vol 13 (9) ◽  
pp. 1780
Author(s):  
Berenike Braun ◽  
Dina Fischer ◽  
Kerstin Laib Sampaio ◽  
Maja Mezger ◽  
Dagmar Stöhr ◽  
...  
Keyword(s):  
Human Cytomegalovirus ◽  
Growth Factor Receptor ◽  
Transmission Mode ◽  
Soluble Form ◽  
Free Virus ◽  
Viral Glycoprotein ◽  
Virus Growth ◽  
Factor Receptor Alpha ◽  
Peptide Derivatives ◽  
Derivatives Of

Cell-free human cytomegalovirus (HCMV) can be inhibited by a soluble form of the cellular HCMV-receptor PDGFRα, resembling neutralization by antibodies. The cell-associated growth of recent HCMV isolates, however, is resistant against antibodies. We investigated whether PDGFRα-derivatives can inhibit this transmission mode. A protein containing the extracellular PDGFRα-domain and 40-mer peptides derived therefrom were tested regarding the inhibition of the cell-associated HCMV strain Merlin-pAL1502, hits were validated with recent isolates, and the most effective peptide was modified to increase its potency. The modified peptide was further analyzed regarding its mode of action on the virion level. While full-length PDGFRα failed to inhibit HCMV isolates, three peptides significantly reduced virus growth. A 30-mer version of the lead peptide (GD30) proved even more effective against the cell-free virus, and this effect was HCMV-specific and depended on the viral glycoprotein O. In cell-associated spread, GD30 reduced both the number of transferred particles and their penetration. This effect was reversible after peptide removal, which allowed the synchronized analysis of particle transfer, showing that two virions per hour were transferred to neighboring cells and one virion was sufficient for infection. In conclusion, PDGFRα-derived peptides are novel inhibitors of the cell-associated spread of HCMV and facilitate the investigation of this transmission mode.

scholarly journals Selection of Human Cytomegalovirus Mutants with Resistance against PDGFRα-Derived Entry Inhibitors

Viruses ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 1094
Author(s):  
Kerstin Laib Sampaio ◽  
Carolin Lutz ◽  
Rebecca Engels ◽  
Dagmar Stöhr ◽  
Christian Sinzger
Keyword(s):  
Human Cytomegalovirus ◽  
Viral Entry ◽  
Growth Factor Receptor ◽  
Genetic Barrier ◽  
Entry Inhibitors ◽  
Factor Receptor Alpha ◽  
Underlying Mechanisms ◽  
Derivatives Of ◽  
Strain Ad169 ◽  
Selection Of

The human cytomegalovirus (HCMV) infects fibroblasts via an interaction of its envelope glycoprotein gO with the cellular platelet-derived growth factor receptor alpha (PDGFRα), and soluble derivatives of this receptor can inhibit viral entry. We aimed to select mutants with resistance against PDGFRα-Fc and the PDGFRα-derived peptides GT40 and IK40 to gain insight into the underlying mechanisms and determine the genetic barrier to resistance. An error-prone variant of strain AD169 was propagated in the presence of inhibitors, cell cultures were monitored weekly for signs of increased viral growth, and selected viruses were tested regarding their sensitivity to the inhibitor. Resistant virus was analyzed by DNA sequencing, candidate mutations were transferred into AD169 clone pHB5 by seamless mutagenesis, and reconstituted virus was again tested for loss of sensitivity by dose-response analyses. An S48Y mutation in gO was identified that conferred a three-fold loss of sensitivity against PDGFRα-Fc, a combination of mutations in gO, gH, gB and gN reduced sensitivity to GT40 by factor 4, and no loss of sensitivity occurred with IK40. The resistance-conferring mutations support the notion that PDGFRα-Fc and GT40 perturb the interaction of gO with its receptor, but the relatively weak effect indicates a high genetic barrier to resistance.

scholarly journals Pathogen at the Gates: Human Cytomegalovirus Entry and Cell Tropism

2018 ◽  
Author(s):  
Christopher C. Nguyen ◽  
Jeremy P. Kamil
Keyword(s):  
Human Cytomegalovirus ◽  
Wide Spectrum ◽  
Growth Factor Receptor ◽  
Cell Types ◽  
Stable Complex ◽  
Cell Tropism ◽  
The Past ◽  
Factor Receptor Alpha ◽  
Glycoprotein H ◽  
Substantial Progress

The past few years have brought substantial progress toward understanding how human cytomegalovirus (HCMV) enters the remarkably wide spectrum of cell types and tissues that the virus infects. Neuropilin-2 and platelet-derived growth factor receptor alpha (PDGFRa) were identified as receptors, respectively, for the trimeric and pentameric glycoprotein H/glycoprotein L (gH/gL) complexes that in large part govern HCMV cell tropism, while CD90 and CD147 were also found to play roles during entry. X-ray crystal structures for the proximal viral fusogen, glycoprotein B (gB), and for the pentameric gH/gL complex (pentamer) have been solved. A novel virion gH complex consisting of gH bound to UL116 instead of gL was described, and findings supporting the existence of a stable complex between gH/gL and gB were reported. Additional work indicates that the pentamer promotes a mode of cell-associated spread that resists antibody neutralization, as opposed to the trimeric gH/gL complex (trimer), which appears to be broadly required for the infectivity of cell-free virions. Finally, viral factors such as UL148 and US16 were identified that can influence the incorporation of the alternative gH/gL complexes into virions. We will review these advances and their implications for understanding HCMV entry and cell tropism.

scholarly journals Transition toward Human Cytomegalovirus Susceptibility in Early Human Embryonic Stem Cell-Derived Neural Precursors

2015 ◽  
Vol 89 (21) ◽  
pp. 11159-11164 ◽  
Author(s):  
Amnon A. Berger ◽  
Yaniv Gil ◽  
Amos Panet ◽  
Yiska Weisblum ◽  
Esther Oiknine-Djian ◽  
...  
Keyword(s):  
Human Cytomegalovirus ◽  
Hcmv Infection ◽  
Embryonic Stem ◽  
Growth Factor Receptor ◽  
Neural Precursors ◽  
Viral Binding ◽  
Factor Receptor Alpha ◽  
Viral Restriction ◽  
Early Human

Congenital human cytomegalovirus (HCMV) infection is associated with neurodevelopmental disabilities. To dissect the earliest events of infection in the developing human brain, we studied HCMV infection during controlled differentiation of human embryonic stem cells (hESC) into neural precursors. We traced a transition from viral restriction in hESC, mediated by a block in viral binding, toward HCMV susceptibility in early hESC-derived neural precursors. We further revealed the role of platelet-derived growth factor receptor alpha (PDGFRα) as a determinant of the developmentally acquired HCMV susceptibility.

scholarly journals Pathogen at the Gates: Human Cytomegalovirus Entry and Cell Tropism

Viruses ◽  
2018 ◽  
Vol 10 (12) ◽  
pp. 704 ◽  
Author(s):  
Christopher Nguyen ◽  
Jeremy Kamil
Keyword(s):  
Human Cytomegalovirus ◽  
Wide Spectrum ◽  
Growth Factor Receptor ◽  
Cell Types ◽  
Stable Complex ◽  
Cell Tropism ◽  
The Past ◽  
Factor Receptor Alpha ◽  
Glycoprotein H ◽  
Substantial Progress

The past few years have brought substantial progress toward understanding how human cytomegalovirus (HCMV) enters the remarkably wide spectrum of cell types and tissues that it infects. Neuropilin-2 and platelet-derived growth factor receptor alpha (PDGFRα) were identified as receptors, respectively, for the trimeric and pentameric glycoprotein H/glycoprotein L (gH/gL) complexes that in large part govern HCMV cell tropism, while CD90 and CD147 were also found to play roles during entry. X-ray crystal structures for the proximal viral fusogen, glycoprotein B (gB), and for the pentameric gH/gL complex (pentamer) have been solved. A novel virion gH complex consisting of gH bound to UL116 instead of gL was described, and findings supporting the existence of a stable complex between gH/gL and gB were reported. Additional work indicates that the pentamer promotes a mode of cell-associated spread that resists antibody neutralization, as opposed to the trimeric gH/gL complex (trimer), which appears to be broadly required for the infectivity of cell-free virions. Finally, viral factors such as UL148 and US16 were identified that can influence the incorporation of the alternative gH/gL complexes into virions. We will review these advances and their implications for understanding HCMV entry and cell tropism.

Synthesis of New Peptide Derivatives of Galanthamine Designed for Prevention and Treatment of Alzheimer’s Disease

2015 ◽  
Vol 22 (10) ◽  
pp. 913-922 ◽  
Author(s):  
Lyubomir Vezenkov ◽  
Lilia Ilieva ◽  
Dancho Danalev ◽  
Anastasia Bakalova ◽  
D. Vassilev ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Prevention And Treatment ◽  
Peptide Derivatives ◽  
Derivatives Of

scholarly journals PDGFRα: Expression and Function during Mitral Valve Morphogenesis

2021 ◽  
Vol 8 (3) ◽  
pp. 28
Author(s):  
Kelsey Moore ◽  
Diana Fulmer ◽  
Lilong Guo ◽  
Natalie Koren ◽  
Janiece Glover ◽  
...  
Keyword(s):  
Mitral Valve ◽  
Primary Cilia ◽  
Growth Factor Receptor ◽  
Akt Phosphorylation ◽  
Valve Development ◽  
Biochemical Assays ◽  
Factor Receptor Alpha ◽  
Mesenchymal Transformation ◽  
And Function

Mitral valve prolapse (MVP) is a common form of valve disease and can lead to serious secondary complications. The recent identification of MVP causal mutations in primary cilia-related genes has prompted the investigation of cilia-mediated mechanisms of disease inception. Here, we investigate the role of platelet-derived growth factor receptor-alpha (PDGFRα), a receptor known to be present on the primary cilium, during valve development using genetically modified mice, biochemical assays, and high-resolution microscopy. While PDGFRα is expressed throughout the ciliated valve interstitium early in development, its expression becomes restricted on the valve endocardium by birth and through adulthood. Conditional ablation of Pdgfra with Nfatc1-enhancer Cre led to significantly enlarged and hypercellular anterior leaflets with disrupted endothelial adhesions, activated ERK1/2, and a dysregulated extracellular matrix. In vitro culture experiments confirmed a role in suppressing ERK1/2 activation while promoting AKT phosphorylation. These data suggest that PDGFRα functions to suppress mesenchymal transformation and disease phenotypes by stabilizing the valve endocardium through an AKT/ERK pathway.

scholarly journals Contribution of PDGFRα-positive cells in maintenance and injury responses in mouse large vessels

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Kenichi Kimura ◽  
Karina Ramirez ◽  
Tram Anh Vu Nguyen ◽  
Yoshito Yamashiro ◽  
Aiko Sada ◽  
...  
Keyword(s):  
Growth Factor Receptor ◽  
Pressure Overload ◽  
Vascular Diseases ◽  
Cell Types ◽  
Lineage Tracing ◽  
Neointima Formation ◽  
Artery Ligation ◽  
Carotid Artery Ligation ◽  
Factor Receptor Alpha ◽  
Adventitial Cells

AbstractThe maladaptive remodeling of vessel walls with neointima formation is a common feature of proliferative vascular diseases. It has been proposed that neointima formation is caused by the dedifferentiation of mature smooth muscle cells (SMCs). Recent evidence suggests that adventitial cells also participate in neointima formation; however, their cellular dynamics are not fully understood. In this study, we utilized a lineage tracing model of platelet-derived growth factor receptor alpha (PDGFRa) cells and examined cellular behavior during homeostasis and injury response. PDGFRa marked adventitial cells that were largely positive for Sca1 and a portion of medial SMCs, and both cell types were maintained for 2 years. Upon carotid artery ligation, PDGFRa-positive (+) cells were slowly recruited to the neointima and exhibited an immature SMC phenotype. In contrast, in a more severe wire denudation injury, PDGFRa+ cells were recruited to the neointima within 14 days and fully differentiated into SMCs. Under pressure overload induced by transverse aortic constriction, PDGFRa+ cells developed marked adventitial fibrosis. Taken together, our observations suggest that PDGFRa+ cells serve as a reservoir of adventitial cells and a subset of medial SMCs and underscore their context-dependent response to vascular injuries.

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