Modeling of the human rhinovirus C capsid suggests a novel topography with insights on receptor preference and immunogenicity

Basta, Holly A.; Sgro, Jean-Yves; Palmenberg, Ann C.

doi:10.1016/j.virol.2013.10.006

Cited by 33 publications

(36 citation statements)

References 39 publications

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“…Of the 4 immunodominant RV-C regions identified in this study, three (C1, C3, and C4) are located in regions presenting species-specific amino acid substitution and one (C2) is located in the VP1 region that had major species C-specific amino acid deletions. Our findings on RV-C-specific T-cell epitopes provide experimental evidence that corroborates the predictions made on the basis of bioinformatics tools (29), which suggested that RV-Cs have new, unique epitopes that are well conserved within species C (29).…”

Section: Discussionsupporting

confidence: 87%

“…4, red boxed regions). Furthermore, species C presents major amino acid deletions, especially in the center of VP1, which shortened the protein by 21 residues compared to VP1 of species A (29). Of the 4 immunodominant RV-C regions identified in this study, three (C1, C3, and C4) are located in regions presenting species-specific amino acid substitution and one (C2) is located in the VP1 region that had major species C-specific amino acid deletions.…”

Section: Discussionmentioning

confidence: 68%

“…However, our results have shown that the RV-A peptides (RVA-9 to -11, RVA-13 and -14, RVA-29 and -30, and RVA-38 to -40) and the RV-C peptides (RVC-9 to -11, RVC-13 and -14, RVC-25 and -26, and RVC-35 and -36) located in the four conserved motifs all presented low immunogenicity, shown by their low reactive scores. The most plausible reason is that well-conserved segments are known to have low immunogenicity, as these regions are not under selective pressure (29). Our study demonstrates that RV-A and -C T-cell epitopes are located in very distinct regions of the VP1 protein that are unique for each species.…”

Section: Discussionmentioning

confidence: 80%

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Immunodominant T-Cell Epitopes in the VP1 Capsid Protein of Rhinovirus Species A and C

Gaido

Stone

Chopra

et al. 2016

J Virol

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Rhinovirus (RV) species A and C are the most frequent cause of respiratory viral illness worldwide, and RV-C has been linked to more severe exacerbations of asthma in young children. Little is known about the immune responses to the different RV species, although studies comparing IgG1 antibody titers found impaired antibody responses to RV-C. Therefore, the aim of this study was to assess whether T-cell immunity to RV-C is similarly impaired. We measured T-cell proliferation to overlapping synthetic peptides covering the entire VP1 capsid protein of an RV-A and RV-C genotype for 20 healthy adult donors. Human leukocyte antigen (HLA) was typed in all the donors in order to investigate possible associations between the HLA type and RV peptide recognition. Total and specific IgG1 antibody titers to the VP1 proteins of both RV-A and RV-C were also measured to examine associations between the antibody and T-cell responses. We identified T-cell epitopes that are specific to and representative of each RV-A and RV-C species. These epitopes stimulated CD4 ؉ -specific T-cell proliferation, with similar magnitudes of response for both RV species. All the donors, independent of their HLA-DR or -DQ type, were able to recognize the immunodominant RV-A and -C regions of VP1. Furthermore, the presence or absence of specific antibody titers was not related to changes in T-cell recognition. Our results indicate a dissociation between the antibody and T-cell responses to rhinoviruses. The species-representative T-cell epitopes identified in this study are valuable tools for future studies investigating T-cell responses to the different RV species. IMPORTANCERhinoviruses (RVs) are mostly associated with the common cold and asthma exacerbations, although their contributions to most upper and lower respiratory tract diseases have increasingly been reported. Species C (RV-C) has been associated with more frequent and severe asthma exacerbations in young children and, along with RV-A, is the most clinically relevant species. Little is known about how our immune system responds to rhinoviruses, and there are limited tools to study specific adaptive immunity against each rhinovirus species. In this study, we identified immunodominant T-cell epitopes of the VP1 proteins of RV-A and RV-C, which are representative of each species. The study found that T-cell responses to RV-A and RV-C were of similar magnitudes, in contrast with previous findings showing RV-C-specific antibody responses were low. These findings will provide the basis for future studies on the immune response to rhinoviruses and can help elucidate the mechanisms of severity of rhinovirus-induced infections.

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Section: Discussionsupporting

confidence: 87%

Section: Discussionmentioning

confidence: 68%

Section: Discussionmentioning

confidence: 80%

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Immunodominant T-Cell Epitopes in the VP1 Capsid Protein of Rhinovirus Species A and C

Gaido

Stone

Chopra

et al. 2016

J Virol

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“…To test the feasibility of virus-receptor interactions, we docked the CDHR3 domains 1, 2, and 3 to a two-protomer model of RV-C15 capsid (23). Preliminary mutagenesis experiments suggested that Asn 186 , but not Trp 86 , was participating in virus binding; therefore, both queried algorithms [Gramm-X (24) and HAD-DOCK (25)] were given only two constraints: (i) CDHR3 Asn 186 should be at or near the interface and (ii) the solvent exposed (outer) surface of the capsid proteins should be involved.…”

Section: Development and Characterization Of Transduced Hela Cell Linementioning

confidence: 99%

“…The RV-C as a species conserves <75% capsid protein identity, but the RV-C15 structure model predicts a single shared receptor (23). The modeled CHDR3 footprint covers nearly every surface residue of RV-C15 that is conserved within the species (Fig.…”

Section: Development and Characterization Of Transduced Hela Cell Linementioning

confidence: 99%

Cadherin-related family member 3, a childhood asthma susceptibility gene product, mediates rhinovirus C binding and replication

Bochkov¹,

Watters

Ashraf³

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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361

345

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Members of rhinovirus C (RV-C) species are more likely to cause wheezing illnesses and asthma exacerbations compared with other rhinoviruses. The cellular receptor for these viruses was heretofore unknown. We report here that expression of human cadherin-related family member 3 (CDHR3) enables the cells normally unsusceptible to RV-C infection to support both virus binding and replication. A coding single nucleotide polymorphism (rs6967330, C529Y) was previously linked to greater cell-surface expression of CDHR3 protein, and an increased risk of wheezing illnesses and hospitalizations for childhood asthma. Compared with wild-type CDHR3, cells transfected with the CDHR3-Y529 variant had about 10-fold increases in RV-C binding and progeny yields. We developed a transduced HeLa cell line (HeLa-E8) stably expressing CDHR3-Y529 that supports RV-C propagation in vitro. Modeling of CDHR3 structure identified potential binding sites that could impact the virus surface in regions that are highly conserved among all RV-C types. Our findings identify that the asthma susceptibility gene product CDHR3 mediates RV-C entry into host cells, and suggest that rs6967330 mutation could be a risk factor for RV-C wheezing illnesses.

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3D Structure, Dimerization Modeling, and Lead Discovery by Ligand‐protein Interaction Analysis of p60 Transcription Regulator Protein (p60TRP)

Pramanik

Kutzner

Heese

2015

Molecular Informatics

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The p60 transcription regulator protein (p60TRP) is a basic helix-loop-helix (bHLH) domain-containing neuroprotective protein and a member of the G-protein-coupled receptor (GPCR)-associated sorting protein (GPRASP) family. In the present study, multiple theoretical physico-chemical methods (e.g. Modeller v.9.13, I-TASSER, PROCHECK and ClusPro v2.0 with PIPER) were applied to unveil the three-dimensional (3D) protein structure of the p60TRP homo-dimer protein and explore potential ligand-protein interactions. Our results suggest a Mg(2+) -containing 3D p60TRP dimer protein that potentially interacts with 5-(1-aziridinyl)-2,4-dinitrobenzamide (CB1954) and [2-(3-dodecylimidazolidin-1-yl)-1-phosphonoethyl] phosphonic acid (B73). The discovery of CB1954 and B73 may serve as a potential lead for further drug screening tests to normalize the p60TRP signaling pathway in neurodegenerative diseases. Interference with p60TRP signaling via CB1954/B73-related molecules might be a novel option for modifying neurodegenerative signaling pathways (e.g. RIN1, PP2A, RanBP5, CREB and SYNJ1) to treat various brain diseases.

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Modeling of the human rhinovirus C capsid suggests a novel topography with insights on receptor preference and immunogenicity

Cited by 33 publications

References 39 publications

Immunodominant T-Cell Epitopes in the VP1 Capsid Protein of Rhinovirus Species A and C

Immunodominant T-Cell Epitopes in the VP1 Capsid Protein of Rhinovirus Species A and C

Cadherin-related family member 3, a childhood asthma susceptibility gene product, mediates rhinovirus C binding and replication

3D Structure, Dimerization Modeling, and Lead Discovery by Ligand‐protein Interaction Analysis of p60 Transcription Regulator Protein (p60TRP)

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