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Equine rhinitis A virus and its low pH empty particle: clues towards an aphthovirus entry mechanism?
Tobias J Tuthill1, Karl Harlos, Thomas S Walter
1Institute of Molecular and Cellular Biology and Astbury Centre for Structural Molecular Biology, Faculty of Biological Sciences, University of Leeds, Leeds, United Kingdom.
Abstract:
Equine rhinitis A virus (ERAV) is closely related to foot-and-mouth disease virus (FMDV), belonging to the genus Aphthovirus of the Picornaviridae. How picornaviruses introduce their RNA genome into the cytoplasm of the host cell to initiate replication is unclear since they have no lipid envelope to facilitate fusion with cellular membranes. It has been thought that the dissociation of the FMDV particle into pentameric subunits at acidic pH is the mechanism for genome release during cell entry, but this raises the problem of how transfer across the endosome membrane of the genome might be facilitated. In contrast, most other picornaviruses form 'altered' particle intermediates (not reported for aphthoviruses) thought to induce membrane pores through which the genome can be transferred. Here we show that ERAV, like FMDV, dissociates into pentamers at mildly acidic pH but demonstrate that dissociation is preceded by the transient formation of empty 80S particles which have released their genome and may represent novel biologically relevant intermediates in the aphthovirus cell entry process. The crystal structures of the native ERAV virus and a low pH form have been determined via highly efficient crystallization and data collection strategies, required due to low virus yields. ERAV is closely similar to FMDV for VP2, VP3 and part of VP4 but VP1 diverges, to give a particle with a pitted surface, as seen in cardioviruses. The low pH particle has internal structure consistent with it representing a pre-dissociation cell entry intermediate. These results suggest a unified mechanism of picornavirus cell entry.
Insights
Equine rhinitis A virus (ERAV) cell entry involves a novel empty 80S particle intermediate. This finding suggests a unified mechanism for picornavirus RNA genome release and host cell entry.
Area of Science:
- Virology
- Structural Biology
- Molecular Biology
Background:
- Picornaviruses, including Equine rhinitis A virus (ERAV) and foot-and-mouth disease virus (FMDV), lack lipid envelopes, making their RNA genome entry into host cells complex.
- The precise mechanism of RNA release and transfer across endosomal membranes during picornavirus infection remains incompletely understood.
- While FMDV is thought to release its genome via pH-dependent dissociation, and other picornaviruses form 'altered' particles, the specific entry pathway for aphthoviruses was unclear.
Purpose of the Study:
- To elucidate the cell entry mechanism of Equine rhinitis A virus (ERAV), an aphthovirus.
- To investigate the structural and functional intermediates involved in ERAV RNA genome release.
- To compare the cell entry pathway of ERAV with other picornaviruses and propose a unified model.
Main Methods:
- High-throughput crystallization and X-ray crystallography were employed to determine the structures of native ERAV and a low pH form.
- Comparative structural analysis of ERAV with related picornaviruses (FMDV, cardioviruses).
- Biochemical assays to characterize pH-dependent particle changes and genome release intermediates.
Main Results:
- ERAV, similar to FMDV, dissociates into pentamers at acidic pH.
- Crucially, ERAV transiently forms empty 80S particles before pentamer dissociation, representing a novel intermediate in aphthovirus entry.
- Structural analysis revealed ERAV shares similarities with FMDV but has a divergent VP1, resulting in a pitted surface, and the low pH structure is consistent with a pre-dissociation intermediate.
Conclusions:
- ERAV cell entry involves a previously undescribed empty 80S particle intermediate, preceding pentamer dissociation.
- This finding suggests a potentially unified mechanism for picornavirus RNA genome release and cell entry across different genera.
- The structural insights into ERAV provide a basis for understanding aphthovirus-host interactions and developing antiviral strategies.
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