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.

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 Pathogen at the Gates: HCMV Entry and Cell Tropism

2018 ◽  
Author(s):  
Christopher C. Nguyen ◽  
Jeremy P. Kamil
Keyword(s):  
Wide Spectrum ◽  
Growth Factor Receptor ◽  
Cell Types ◽  
Stable Complex ◽  
Cell Tropism ◽  
X Ray ◽  
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 is observed to infect.  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) were 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 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.

scholarly journals Cryo-Electron Microscopy Structure and Interactions of the Human Cytomegalovirus gHgLgO Trimer with Platelet-Derived Growth Factor Receptor Alpha

mBio ◽  
2021 ◽  
Vol 12 (5) ◽  
Author(s):  
Jing Liu ◽  
Adam Vanarsdall ◽  
Dong-Hua Chen ◽  
Andrea Chin ◽  
David Johnson ◽  
...  
Keyword(s):  
Birth Defects ◽  
Adult Population ◽  
Growth Factor Receptor ◽  
Cell Types ◽  
The Body ◽  
Platelet Derived Growth Factor ◽  
Cryo Electron Microscopy ◽  
Factor Receptor Alpha ◽  
Complex Protein ◽  
Different Cell Types

HCMV is a herpesvirus that infects a large percentage of the adult population and causes significant levels of disease in immunocompromised individuals and birth defects in the developing fetus. The virus encodes a complex protein machinery that coordinates infection of different cell types in the body, including a trimer formed of gH, gL, and gO subunits.

Abstract 92: Platelet Derived Growth Factor Receptor Alpha Signaling is Required for Cardiac Fibroblast Survival and Proliferation

2016 ◽  
Vol 119 (suppl_1) ◽  
Author(s):  
Malina J Ivey ◽  
Michelle D Tallquist
Keyword(s):  
Preliminary Data ◽  
Cardiac Fibrosis ◽  
Heart Function ◽  
Cardiac Fibroblasts ◽  
Growth Factor Receptor ◽  
Cell Types ◽  
Fibroblast Proliferation ◽  
Artery Ligation ◽  
Developing Heart ◽  
Factor Receptor Alpha

Cardiac fibrosis contributes significantly to heart disease and is a hallmark of decreased cardiac function. Currently, there are no treatments that attenuate fibrosis, but identification of signaling pathways required for fibroblast function would provide some potential targets. PDGFRα is a receptor tyrosine kinase that is required for fibroblast formation in the developing heart, and preliminary data indicates that it is also required for maintenance of resident fibroblasts and expansion of activated fibroblasts after injury. Preliminary experiments demonstrate that loss of PDGFRα expression in adult cardiac fibroblasts results in 50% reduction in the number of the resident fibroblasts by 4 days after gene deletion. This was further validated using an independent fibroblast marker, collagen1a1GFP. Based on the low basal level of fibroblast proliferation, we hypothesize that PDGFRα signaling is essential for fibroblast survival and that fibroblasts undergo rapid turnover in the absence of PDGFRα signaling. Future studies will determine the exact mechanism of this loss. We have also begun to elucidate which PDGFRα downstream signals promote fibroblast maintenance. Using a PDGFRα-dependent-PI3K-deficient mouse model, preliminary data indicates that PDGFRα-dependent PI3K signaling is essential for cell survival. We are also investigating the role of PDGFRα signaling after myocardial infarction. Using recently described genetic tools to follow fibroblasts after injury, we have determined that fibroblasts reach their peak of proliferation within a week after permanent left anterior descending artery ligation. This injury-induced proliferation is reduced by 50% after deletion of PDGFRα. Therefore, we have demonstrated that PDGFRα has a role in fibroblast maintenance in the healthy heart, as well as a role in fibroblast proliferation after injury. Our studies will continue to illuminate additional roles for PDGFRα in the fibroblast, as well as the implications of fibroblast loss on other cell types and overall heart function.

scholarly journals Polymorphisms in Human Cytomegalovirus gO Exert Epistatic Influences on Cell-Free and Cell-To-Cell Spread, and Antibody Neutralization on gH Epitopes

2019 ◽  
Author(s):  
Le Zhang Day ◽  
Cora Stegmann ◽  
Eric P. Schultz ◽  
Jean-Marc Lanchy ◽  
Qin Yu ◽  
...  
Keyword(s):  
Human Cytomegalovirus ◽  
Viral Genome ◽  
Genetic Background ◽  
Neutralizing Antibodies ◽  
Important Determinant ◽  
Cell Types ◽  
Cell Tropism ◽  
Laboratory Studies ◽  
Antibody Neutralization ◽  
Cell Spread

ABSTRACTThe human cytomegalovirus (HCMV) glycoproteins H and L (gH/gL) can be bound by either gO, or the UL128-131 proteins to form complexes that facilitate entry and spread and the complexes formed are important targets of neutralizing antibodies. Strains of HCMV vary considerably in the levels of gH/gL/gO and gH/gL/UL128-131 and this can impact infectivity and cell tropism. In this report, we investigated how natural interstrain variation in the amino acid sequence of gO influences the biology of HCMV. Heterologous gO recombinants were constructed in which 6 of the 8 alleles or genotypes (GT) of gO were analyzed in the backgrounds of strain TR and Merlin (ME). The levels of gH/gL complexes were not affected, but there were impacts on entry, spread and neutralization by anti-gH antibodies. AD169 (AD) gO (GT1a) drastically reduced cell-free infectivity of both strains on fibroblasts and epithelial cells. PHgO(GT2a) increased cell-free infectivity of TR in both cell types, but spread in fibroblasts was impaired. In contrast, spread of ME in both cell types was enhanced by Towne (TN) gO (GT4), despite similar cell-free infectivity. TR expressing TNgO(GT4) was resistant to neutralization by anti-gH antibodies AP86 and 14-4b, whereas ADgO(GT1a) conferred resistance to 14-4b, but enhanced neutralization by AP86. Conversely, ME expressing ADgO(GT1a) was more resistant to 14-4b. These results suggest; 1) mechanistically distinct roles for gH/gL/gO in cell-free and cell-to-cell spread, 2) gO isoforms can differentially shield the virus from neutralizing antibodies, and 3) effects of gO polymorphisms are epistatically dependent on other variable loci.IMPORTANCEAdvances in HCMV population genetics have greatly outpaced understanding of the links between genetic diversity and phenotypic variation. Moreover, recombination between genotypes may shuffle variable loci into various combinations with unknown outcomes. UL74(gO) is an important determinant of HCMV infectivity, and one of the most diverse loci in the viral genome. By analyzing interstrain heterologous UL74(gO) recombinants, we show that gO diversity can have dramatic impacts on cell-free and cell-to-cell spread as well as on antibody neutralization and that the manifestation of these impacts can be subject to epistatic influences of the global genetic background. These results highlight the potential limitations of laboratory studies of HCMV biology that use single, isolated genotypes or strains.

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 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 Polymorphisms in Human Cytomegalovirus Glycoprotein O (gO) Exert Epistatic Influences on Cell-Free and Cell-to-Cell Spread and Antibody Neutralization on gH Epitopes

2020 ◽  
Vol 94 (8) ◽  
Author(s):  
Le Zhang Day ◽  
Cora Stegmann ◽  
Eric P. Schultz ◽  
Jean-Marc Lanchy ◽  
Qin Yu ◽  
...  
Keyword(s):  
Human Cytomegalovirus ◽  
Viral Genome ◽  
Genetic Background ◽  
Neutralizing Antibodies ◽  
Important Determinant ◽  
Cell Types ◽  
Cell Tropism ◽  
Laboratory Studies ◽  
Antibody Neutralization ◽  
Cell Spread

ABSTRACT Human cytomegalovirus (HCMV) glycoproteins H and L (gH/gL) can be bound by either gO or the UL128 to UL131 proteins (referred to here as UL128-131) to form complexes that facilitate entry and spread, and the complexes formed are important targets of neutralizing antibodies. Strains of HCMV vary considerably in the levels of gH/gL/gO and gH/gL/UL128-131, and this can impact infectivity and cell tropism. In this study, we investigated how natural interstrain variation in the amino acid sequence of gO influences the biology of HCMV. Heterologous gO recombinants were constructed in which 6 of the 8 alleles or genotypes (GT) of gO were analyzed in the backgrounds of strains TR and Merlin (ME). The levels of gH/gL complexes were not affected, but there were impacts on entry, spread, and neutralization by anti-gH antibodies. AD169 (AD) gO (GT1a) [referred to here as ADgO(GT1a)] drastically reduced cell-free infectivity of both strains on fibroblasts and epithelial cells. PHgO(GT2a) increased cell-free infectivity of TR in both cell types, but spread in fibroblasts was impaired. In contrast, spread of ME in both cell types was enhanced by Towne (TN) gO (GT4), despite similar cell-free infectivity. TR expressing TNgO(GT4) was resistant to neutralization by anti-gH antibodies AP86 and 14-4b, whereas ADgO(GT1a) conferred resistance to 14-4b but enhanced neutralization by AP86. Conversely, ME expressing ADgO(GT1a) was more resistant to 14-4b. These results suggest that (i) there are mechanistically distinct roles for gH/gL/gO in cell-free and cell-to-cell spread, (ii) gO isoforms can differentially shield the virus from neutralizing antibodies, and (iii) effects of gO polymorphisms are epistatically dependent on other variable loci. IMPORTANCE Advances in HCMV population genetics have greatly outpaced understanding of the links between genetic diversity and phenotypic variation. Moreover, recombination between genotypes may shuffle variable loci into various combinations with unknown outcomes. UL74(gO) is an important determinant of HCMV infectivity and one of the most diverse loci in the viral genome. By analyzing interstrain heterologous UL74(gO) recombinants, we showed that gO diversity can have dramatic impacts on cell-free and cell-to-cell spread as well as on antibody neutralization and that the manifestation of these impacts can be subject to epistatic influences of the global genetic background. These results highlight the potential limitations of laboratory studies of HCMV biology that use single, isolated genotypes or strains.

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