A molecular understanding of alphavirus entry

Holmes, Autumn C.; Basore, Katherine; Fremont, Daved H.; Diamond, Michael S.

doi:10.1371/journal.ppat.1008876

Cited by 71 publications

(66 citation statements)

References 145 publications

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“…Some viruses that do not require binding to HSPGs to attach and to infect host cells may acquire HSPG dependence following intra-host or cell culture adaptation. There is abundant evidence that several viruses—including rhinoviruses [ 79 , 80 ], Coxsackie virus B3 [ 81 ], Sindbis virus [ 82 , 83 ], Ross River alphavirus [ 84 ], flavivirus tick-borne encephalitis virus [ 85 , 86 ], and others—during repeated passage in cell culture undergo adaptation changes leading to an augmented ability to binding HS, a phenomenon that may provide a selective advantage to the viruses [ 25 ]. Similar viral adaptations occurring in cell cultures may also take place during human infections, generating viral variants that can show different tropism, virulence, and pathogenicity than parental viruses [ 25 , 87 , 88 , 89 , 90 , 91 ].…”

Section: Molecular Mechanisms By Which Viruses Exploit Heparan Sulfate Proteoglycans To Infect Host Cellsmentioning

confidence: 99%

Heparan Sulfate Proteoglycans in Viral Infection and Treatment: A Special Focus on SARS-CoV-2

Pasquale

Quiccione

Tafuri

et al. 2021

IJMS

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Heparan sulfate proteoglycans (HSPGs) encompass a group of glycoproteins composed of unbranched negatively charged heparan sulfate (HS) chains covalently attached to a core protein. The complex HSPG biosynthetic machinery generates an extraordinary structural variety of HS chains that enable them to bind a plethora of ligands, including growth factors, morphogens, cytokines, chemokines, enzymes, matrix proteins, and bacterial and viral pathogens. These interactions translate into key regulatory activity of HSPGs on a wide range of cellular processes such as receptor activation and signaling, cytoskeleton assembly, extracellular matrix remodeling, endocytosis, cell-cell crosstalk, and others. Due to their ubiquitous expression within tissues and their large functional repertoire, HSPGs are involved in many physiopathological processes; thus, they have emerged as valuable targets for the therapy of many human diseases. Among their functions, HSPGs assist many viruses in invading host cells at various steps of their life cycle. Viruses utilize HSPGs for the attachment to the host cell, internalization, intracellular trafficking, egress, and spread. Recently, HSPG involvement in the pathogenesis of SARS-CoV-2 infection has been established. Here, we summarize the current knowledge on the molecular mechanisms underlying HSPG/SARS-CoV-2 interaction and downstream effects, and we provide an overview of the HSPG-based therapeutic strategies that could be used to combat such a fearsome virus.

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Section: Molecular Mechanisms By Which Viruses Exploit Heparan Sulfate Proteoglycans To Infect Host Cellsmentioning

confidence: 99%

Heparan Sulfate Proteoglycans in Viral Infection and Treatment: A Special Focus on SARS-CoV-2

Pasquale

Quiccione

Tafuri

et al. 2021

IJMS

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“…The E2 and E1 proteins associate as heterodimers during biosynthesis, and these then assemble into trimers to form spike structures on the virus surface. Alphavirus entry is initiated by the key step of virus binding to cell surface receptors (entry pathway reviewed in [ 12 , 13 , 14 ]). Virus-receptor binding is followed by clathrin-mediated uptake of the virus into the endosome compartment, where acidic pH promotes the target membrane insertion and refolding of the E1 fusion protein.…”

Section: Introductionmentioning

confidence: 99%

“…Matrix remodeling associated protein 8 (MXRA8) is a well characterized receptor for CHIKV and several other arthritogenic alphaviruses (reviewed in [ 12 ]). The ectodomain of MXRA8 is composed of 2 Ig-like domains that interact with E2-E1 heterodimers to facilitate CHIKV attachment and infection of cells in culture [ 15 , 16 , 17 ].…”

Section: Introductionmentioning

confidence: 99%

“…Conversely, about a 1 log decrease in CHIKV infection is observed when MXRA8 is deleted from an expressing cell line such as mouse embryo fibroblasts [ 15 ]. The residual infection may reflect virus attachment to other molecules (reviewed in [ 12 ]). Together the data show that MXRA8 levels in a target cell line significantly contribute to its usefulness in CHIKV propagation and entry studies.…”

Section: Introductionmentioning

confidence: 99%

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BHK-21 Cell Clones Differ in Chikungunya Virus Infection and MXRA8 Receptor Expression

Yin

Kielian

2021

Viruses

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Baby hamster kidney-21 (BHK-21) cells are widely used to propagate and study many animal viruses using infection and transfection techniques. Among various BHK-21 cell clones, the fibroblast-like BHK-21/C-13 line and the epithelial-like BHK-21/WI-2 line are commonly used cell clones for alphavirus research. Here we report that BHK-21/WI-2 cells were significantly less susceptible to primary infection by the alphavirus chikungunya virus (CHIKV) than were BHK-21/C-13 cells. The electroporation efficiency of alphavirus RNA into BHK-21/WI-2 was also lower than that of BHK-21/C-13. The growth of CHIKV was decreased in BHK-21/WI-2 compared to BHK-21/C-13, while primary infection and growth of the alphavirus Sindbis virus (SINV) were equivalent in the two cell lines. Our results suggested that CHIKV entry could be compromised in BHK-21/WI-2. Indeed, we found that the mRNA level of the CHIKV receptor MXRA8 in BHK-21/WI-2 cells was much lower than that in BHK-21/C-13 cells, and exogenous expression of either human MXRA8 or hamster MXRA8 rescued CHIKV infection. Our results affirm the importance of the MXRA8 receptor for CHIKV infection, and document differences in its expression in two clonal cell lines derived from the original BHK-21 cell cultures. Our results also indicate that CHIKV propagation and entry studies in BHK-21 cells will be significantly more efficient in BHK-21/C-13 than in BHK-21/WI-2 cells.

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“…Natural epidemics of these viruses have identified key residues in the viral glycoproteins that promote virus transmission and infectivity. These findings along with years of extensive experimentation have defined the viral glycoproteins as critical factors for virus assembly, attachment and entry, transmission, and pathogenesis [12][13][14][15][16][17][18].…”

Section: Introductionmentioning

confidence: 99%

Structurally conserved domains between flavivirus and alphavirus fusion glycoproteins contribute to replication in mammals and infectious virion production

Rangel

Catanzaro

Thannickal

et al. 2021

Preprint

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Alphaviruses and flaviviruses have class II fusion glycoproteins that are essential for virion assembly and infectivity. Importantly, the tip of domain II is structurally conserved between the alphavirus and flavivirus fusion proteins, yet whether these structural similarities between virus families translate to functional similarities is unclear. Using in vivo evolution of Zika virus (ZIKV), we identified several novel emerging variants including an envelope glycoprotein variant in b-strand c (V114M) of domain II. We have previously shown that the analogous b-strand c and the ij loop, located in the tip of domain II of the alphavirus E1 glycoprotein, are important for infectivity. This led us to hypothesize that flavivirus E b-strand c also contributes to flavivirus infection. We generated this ZIKV glycoprotein variant and found that while it had little impact on infection in mosquitoes, it reduced replication in human cells and mice, and increased virus sensitivity to ammonium chloride, as seen for alphaviruses. In light of these results and given our alphavirus ij loop studies, we mutated a conserved alanine at the tip of the flavivirus ij loop to valine to test its effect on ZIKV infectivity. Interestingly, this mutation inhibited infectious virion production of ZIKV and yellow fever virus, but not West Nile virus. Together, these studies show that structurally analogous residues in the alphavirus and flavivirus class II fusion proteins contribute to virus infection in vivo and highlight these shared domains as targets for broad-spectrum arbovirus therapies.

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A molecular understanding of alphavirus entry

Cited by 71 publications

References 145 publications

Heparan Sulfate Proteoglycans in Viral Infection and Treatment: A Special Focus on SARS-CoV-2

Heparan Sulfate Proteoglycans in Viral Infection and Treatment: A Special Focus on SARS-CoV-2

BHK-21 Cell Clones Differ in Chikungunya Virus Infection and MXRA8 Receptor Expression

Structurally conserved domains between flavivirus and alphavirus fusion glycoproteins contribute to replication in mammals and infectious virion production

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