Equine Rhinitis A Virus and Its Low pH Empty Particle: Clues Towards an Aphthovirus Entry Mechanism?

Tuthill, Tobias J.; Harlos, K.; Walter, Thomas S.; Knowles, Nick J.; Groppelli, Elisabetta; Rowlands, David J.; Stuart, David I.; Fry, Elizabeth E.

doi:10.1371/journal.ppat.1000620

Cited by 61 publications

(105 citation statements)

References 51 publications

(67 reference statements)

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“…The resulting empty capsids are conventionally referred to as B particles (19). Acidic pH in the endosomes also induces the genome release of the aphthoviruses foot and mouth disease virus (FMDV) and equine rhinitis A virus (ERAV) (28)(29)(30). However, aphthovirus genome release is not connected to capsid expansion or the formation of stable openings in the capsid.…”

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confidence: 99%

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Cryo-EM study of slow bee paralysis virus at low pH reveals iflavirus genome release mechanism

Kalynych

Füzik

Přidal

et al. 2017

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

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Viruses from the family Iflaviridae are insect pathogens. Many of them, including slow bee paralysis virus (SBPV), cause lethal diseases in honeybees and bumblebees, resulting in agricultural losses. Iflaviruses have nonenveloped icosahedral virions containing single-stranded RNA genomes. However, their genome release mechanism is unknown. Here, we show that low pH promotes SBPV genome release, indicating that the virus may use endosomes to enter host cells. We used cryo-EM to study a heterogeneous population of SBPV virions at pH 5.5. We determined the structures of SBPV particles before and after genome release to resolutions of 3.3 and 3.4 Å, respectively. The capsids of SBPV virions in low pH are not expanded. Thus, SBPV does not appear to form "altered" particles with pores in their capsids before genome release, as is the case in many related picornaviruses. The egress of the genome from SBPV virions is associated with a loss of interpentamer contacts mediated by N-terminal arms of VP2 capsid proteins, which result in the expansion of the capsid. Pores that are 7 Å in diameter form around icosahedral threefold symmetry axes. We speculate that they serve as channels for the genome release. Our findings provide an atomic-level characterization of the genome release mechanism of iflaviruses.electron microscopy | uncoating | honeybee | structure | virus

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confidence: 99%

“…However, aphthovirus genome release is not connected to capsid expansion or the formation of stable openings in the capsid. Furthermore, FMDV and ERAV empty capsids rapidly dissociate into pentamers after the genome release (28)(29)(30).…”

mentioning

confidence: 99%

Cryo-EM study of slow bee paralysis virus at low pH reveals iflavirus genome release mechanism

Kalynych

Füzik

Přidal

et al. 2017

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

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“…Enteroviruses and possibly aphtoviruses, such as equine rhinitis A virus or the closely related foot and mouth disease virus follow a stepwise uncoating program leading to empty and eventually disintegrated capsids [4]. A well-defined sequence of structural transitions of PV occurs when the virus binds the poliovirus receptor (PVR/CD155/nectin) and this enables the virus RNA to penetrate the membrane.…”

Section: Uncoating Cues From Receptorsmentioning

confidence: 99%

Uncoating of non-enveloped viruses

Suomalainen¹,

Greber²

2013

Current Opinion in Virology

103

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Non-enveloped viruses enclose their genome in capsids built of repetitive polypeptides interlinked with cementing proteins, divalent cations or disulphides. Interactions are broken in a stepwise manner during entry into cells leading to genome uncoating. Receptor or proteases induce conformational changes in case of rhinovirus, poliovirus or adenovirus, and thereby provide direct uncoating cues. Chemical cues from low endosomal pH activate rhinovirus or aphtovirus, and oxido-reductases mediate disulphide reshuffling of polyomavirus. Cellular motors provide a third class of cues as shown by adenoviruses. These examples highlight the diversity of cellular factors triggering virus uncoating, and offer new perspectives for the development of antivirals.

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“…Both ERAV and FMDV dissociate into pentameric capsid subunits at low pH and this was thought to be the mechanism for genome release from the particle. However, we also recently demonstrated the existence of a low-pH-derived empty particle of ERAV that had lost its RNA, indicating that genome release and capsid dissociation may be distinct events, and the structure of a low-pH particle also provided clues to the mechanism of capsid dissociation (Tuthill et al, 2009). …”

mentioning

confidence: 93%

“…(bond lengths). Although the crystals were grown at low pH, a comparison with the native structure showed no significant changes in the vicinity of the receptorbinding site (Tuthill et al, 2009). …”

mentioning

confidence: 99%

Crystal structure of equine rhinitis A virus in complex with its sialic acid receptor

Fry

Tuthill

Harlos

et al. 2010

Journal of General Virology

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Equine rhinitis A virus (ERAV) shares many features with foot-and-mouth disease virus (FMDV) and both are classified within the genus Aphthovirus of the family Picornaviridae. ERAV is used as a surrogate for FMDV research as it does not require high-level biosecurity. In contrast to FMDV, which uses integrins as cellular receptors, the receptor for ERAV has been reported to involve the sugar moiety sialic acid. This study confirmed the importance of sialic acid for cell entry by ERAV and reports the crystal structure of ERAV particles complexed with the receptor analogue 39-sialyllactose. The receptor is attached to the rim of a capsid pit adjacent to the major immunogenic site and distinct from the sialic acid binding site used by a related picornavirus, the cardiovirus Theiler's murine encephalitis virus. The structure of the major antigenic determinant of the virus, previously identified from antibody escape mutations, is also described as the EF loop of VP1, which forms a hairpin stretching across the capsid surface close to the icosahedral fivefold axis, neighbouring the receptor-binding site, and spanning two protomeric units. INTRODUCTIONEquine rhinitis A virus (ERAV) is one of several picornaviruses that cause cold-like symptoms in horses. ERAV is genetically most closely related to foot-and-mouth disease virus (FMDV) and both viruses are classified within the genus Aphthovirus. The virus contains a positive-sense RNA genome of approximately 7700 nt with a genome organization broadly typical of picornaviruses. The genome is contained within a non-enveloped icosahedral capsid comprising 60 copies of each of the viral proteins: VP1, VP2, VP3 and VP4. In all picornaviruses, VP1-3 adopt the typical viral eight-stranded b-barrel fold with the loops connecting the strands (labelled B-I). The surface-exposed loops together with the C termini define the antigenic phenotype of the virus. We have recently determined the crystallographic structure of ERAV, which showed a broad similarity to FMDV, with the most significant differences relating to the increased length and conformation of the surface loops in VP1 (Tuthill et al., 2009). Both ERAV and FMDV dissociate into pentameric capsid subunits at low pH and this was thought to be the mechanism for genome release from the particle. However, we also recently demonstrated the existence of a low-pH-derived empty particle of ERAV that had lost its RNA, indicating that genome release and capsid dissociation may be distinct events, and the structure of a low-pH particle also provided clues to the mechanism of capsid dissociation (Tuthill et al., 2009).ERAV and FMDV share a number of distinctive physical properties such as buoyant density, base composition and acid lability, as well as biological properties such as a broad host-cell range and the propensity for persistent infection. However, the disease caused by ERAV is quite different to that caused by FMDV and hence it is not surprising that the receptors utilized by these viruses differ.FMDV field viruses are dependen...

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Equine Rhinitis A Virus and Its Low pH Empty Particle: Clues Towards an Aphthovirus Entry Mechanism?

Cited by 61 publications

References 51 publications

Cryo-EM study of slow bee paralysis virus at low pH reveals iflavirus genome release mechanism

Cryo-EM study of slow bee paralysis virus at low pH reveals iflavirus genome release mechanism

Uncoating of non-enveloped viruses

Crystal structure of equine rhinitis A virus in complex with its sialic acid receptor

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