Structural Analysis of a Rabbit Hemorrhagic Disease Virus Binding to Histo-Blood Group Antigens

Leuthold, Mila M.; Dalton, Kevin P.; Hansman, Grant S.

doi:10.1128/jvi.02832-14

Cited by 24 publications

(21 citation statements)

References 41 publications

(64 reference statements)

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“…When the sequence comparison is restricted to the 7 regions of the P domain that show the highest degree of genetic variation (regions V1 to V7 [ 12 ]), the identity between RHDV2 and RHDV strains drops to 60% [ 14 ]. Moreover, the crystallographic resolution of the VP60 protruding P domains of RHDV [ 12 ] and RHDV2 [ 29 ], has enabled the analysis of structural differences between both viruses. Although their overall structures are similar, the P1 subdomain helices are slightly shifted and some P2 subdomain loops are oriented differently.…”

Section: Discussionmentioning

confidence: 99%

Comparative analysis of rabbit hemorrhagic disease virus (RHDV) and new RHDV2 virus antigenicity, using specific virus-like particles

Bárcena¹,

Guerra²,

Ângulo³

et al. 2015

Vet Res

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In 2010 a new Lagovirus related to rabbit haemorrhagic disease virus (RHDV) emerged in France and has since rapidly spread throughout domestic and wild rabbit populations of several European countries. The new virus, termed RHDV2, exhibits distinctive genetic, antigenic and pathogenic features. Notably, RHDV2 kills rabbits previously vaccinated with RHDV vaccines. Here we report for the first time the generation and characterization of RHDV2-specific virus-like particles (VLPs). Our results further confirmed the differential antigenic properties exhibited by RHDV and RHDV2, highlighting the need of using RHDV2-specific diagnostic assays to monitor the spread of this new virus.

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Section: Discussionmentioning

confidence: 99%

Comparative analysis of rabbit hemorrhagic disease virus (RHDV) and new RHDV2 virus antigenicity, using specific virus-like particles

Bárcena¹,

Guerra²,

Ângulo³

et al. 2015

Vet Res

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“…The P domain, which is connected to the S domain via a flexible hinge region, usually contains ␤-barrel-like structures unique to caliciviruses. The P domain can be further divided into two subdomains termed P1 and P2, where the P2 subdomain is mainly responsible for host factor interactions (7)(8)(9). The P2 subdomain is likely an insertion in the P1 subdomain, and the sequence of the P1 subdomain is separated into two parts, N-terminal P1-1 and C-terminal P1-2, with the P2 subdomain positioned in the middle.…”

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confidence: 99%

Antigenic and Cryo-Electron Microscopy Structure Analysis of a Chimeric Sapovirus Capsid

Miyazaki

Taylor

Hansman

et al. 2016

J Virol

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The capsid protein (VP1) of all caliciviruses forms an icosahedral particle with two principal domains, shell (S) and protruding (P) domains, which are connected via a flexible hinge region. The S domain forms a scaffold surrounding the nucleic acid, while the P domains form a homodimer that interacts with receptors. The P domain is further subdivided into two subdomains, termed P1 and P2. The P2 subdomain is likely an insertion in the P1 subdomain; consequently, the P domain is divided into the P1-1, P2, and P1-2 subdomains. In order to investigate capsid antigenicity, N-terminal (N-term)/S/P1-1 and P2/P1-2 were switched between two sapovirus genotypes GI.1 and GI.5. The chimeric VP1 constructs were expressed in insect cells and were shown to self-assemble into virus-like particles (VLPs) morphologically similar to the parental VLPs. Interestingly, the chimeric VLPs had higher levels of cross-reactivities to heterogeneous antisera than the parental VLPs. In order to better understand the antigenicity from a structural perspective, we determined an intermediate-resolution (8.5-Å) cryo-electron microscopy (cryo-EM) structure of a chimeric VLP and developed a VP1 homology model. The cryo-EM structure revealed that the P domain dimers were raised slightly (ϳ5 Å) above the S domain. The VP1 homology model allowed us predict the S domain (67-229) and P1-1 (229 -280), P2 (281-447), and P1-2 (448 -567) subdomains. Our results suggested that the raised P dimers might expose immunoreactive S/P1-1 subdomain epitopes. Consequently, the higher levels of cross-reactivities with the chimeric VLPs resulted from a combination of GI.1 and GI.5 epitopes. IMPORTANCEWe developed sapovirus chimeric VP1 constructs and produced the chimeric VLPs in insect cells. We found that both chimeric VLPs had a higher level of cross-reactivity against heterogeneous VLP antisera than the parental VLPs. The cryo-EM structure of one chimeric VLP (Yokote/Mc114) was solved to 8.5-Å resolution. A homology model of the VP1 indicated for the first time the putative S and P (P1-1, P2, and P1-2) domains. The overall structure of Yokote/Mc114 contained features common among other caliciviruses. We showed that the P2 subdomain was mainly involved in the homodimeric interface, whereas a large gap between the P1 subdomains had fewer interactions. Human sapovirus (genus Sapovirus) is a causative agent of gastroenteritis and a member of the Caliciviridae family. Other genera in the Caliciviridae family include Norovirus, Vesivirus, Lagovirus, and Nebovirus. The genomic organizations of all caliciviruses are similar, with the 5= half encoding the nonstructural proteins and the 3= half encoding structural proteins, including the capsid protein (VP1) and a small unknown structural protein, termed VP2 (reviewed in reference 1). Human sapovirus cannot be grown in cell culture, but expression of the VP1 in insect cells results in the formation of virus-like particles (VLPs) that are morphologically and antigenically similar to the native virions (2). There ar...

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“…Clearly, the ability to recognize HBGA glycan motifs shared by pathogenic and nonpathogenic strains indicates that it does not constitute a virulence factor and therefore cannot explain the acquisition of virulence by some strains. Cocrystallization of the P domain from a GI.2 strain with the H type 2 trisaccharide allowed characterization of the carbohydratebinding site (77). Examination of presently available protein sequences indicated that the main amino acids involved in glycan binding are conserved across all lagoviruses, including GI and GII.…”

Section: Discussionmentioning

confidence: 99%

Host-Specific Glycans Are Correlated with Susceptibility to Infection by Lagoviruses, but Not with Their Virulence

Lopes

Breiman

Lora

et al. 2018

J Virol

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The rabbit hemorrhagic disease virus (RHDV) and the European brown hare syndrome virus (EBHSV) are two lagoviruses from the family that cause fatal diseases in two leporid genera, and , respectively. In the last few years, several examples of host jumps of lagoviruses among leporids were recorded. In addition, a new pathogenic genotype of RHDV emerged and many non-pathogenic strains of lagoviruses have been described. The molecular mechanisms behind host shifts and the emergence of virulence are unknown. Since RHDV uses glycans of the histo-blood group antigen type as attachment factors to initiate infection, we studied if glycan specificities of the new pathogenic RHDV genotype, non-pathogenic lagoviruses and EBHSV potentially play a role in determining host range and virulence of lagoviruses. We observed binding to A, B or H antigens of the histo-blood group family for all strains known to primarily infect European rabbits (), that have recently been classified as GI strains. Yet, we could not explain the emergence of virulence since similar glycan specificities were found between several pathogenic and non-pathogenic strains. By contrast, EBHSV, recently classified as GII.1, bound to terminal β-linked N-acetylglucosamine residues of O-glycans. Expression of these attachment factors in the upper respiratory and digestive tracts in three lagomorph species ( and ) showed species-specific patterns regarding the susceptibility to infection by these viruses, indicating that species-specific glycan expression is likely a major contributor to lagoviruses host specificity and range. Lagoviruses constitute a genus of the family, comprising highly pathogenic viruses, RHDV and EBHSV, which infect rabbits and hares, respectively. Recently, non-pathogenic strains were discovered and new pathogenic strains have emerged. In addition, host jumps between lagomorphs are observed. The mechanisms responsible for the emergence of pathogenicity and host-species range are unknown. Previous studies showed that RHDV strains attach to glycans expressed in the upper respiratory and digestive tracts of rabbits, the likely doors of virus entry. Here we studied the glycan-binding properties of novel pathogenic and non-pathogenic strains looking for a link between glycan-binding and virulence or between glycan specificity and host range. We found that glycan binding did not correlate with virulence. However, expression of glycan motifs in the upper respiratory and digestive tracts of lagomorphs revealed species-specific patterns associated with the host range of the virus strains, suggesting that glycan diversity contributes to lagoviruses' host range.

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Structural Analysis of a Rabbit Hemorrhagic Disease Virus Binding to Histo-Blood Group Antigens

Cited by 24 publications

References 41 publications

Comparative analysis of rabbit hemorrhagic disease virus (RHDV) and new RHDV2 virus antigenicity, using specific virus-like particles

Comparative analysis of rabbit hemorrhagic disease virus (RHDV) and new RHDV2 virus antigenicity, using specific virus-like particles

Antigenic and Cryo-Electron Microscopy Structure Analysis of a Chimeric Sapovirus Capsid

Host-Specific Glycans Are Correlated with Susceptibility to Infection by Lagoviruses, but Not with Their Virulence

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