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ERC

PICOSTRUCTURE Report Summary

Project ID: 335855
Funded under: FP7-IDEAS-ERC
Country: Czech Republic

Mid-Term Report Summary - PICOSTRUCTURE (Structural studies of human picornaviruses)

The project “PicoStructure” is focused on determining molecular mechanisms necessary for replication of small non-enveloped viruses from the order Picornavirales. These viruses cause diseases in humans and animals. We aim to provide structural information that will allow subsequent development of anti-viral drugs and vaccines.
Diseases caused by human picornaviruses range from upper and lower respiratory tract infections to encephalitis. Currently there are no anti-viral drugs approved against picornavirus infections and the available treatments are only symptomatic. Other viruses from the order picornavirales are economically important pathogens of honeybees. About 10% of the total economic value of agricultural production depends on honeybee pollination. Abundance of insect pollinated plant species declines in areas with reduced populations of honeybees. Prior to the initiation of our research project there was no structural information about virions of honeybee viruses.
We determined virion structures of three human viruses: parechovirus 1, aichi virus 1, and saffold virus 3.
(1) Human parechoviruses (HPeVs) are pathogens that cause diseases ranging from respiratory and gastrointestinal disorders to encephalitis. Recently, there have been outbreaks of HPeV infections in Western Europe and North America. The structure of HPeV-1 explains why it cannot be targeted by antiviral compounds that are effective against other picornaviruses. Furthermore, we found that the interactions of the HPeV-1 genome with the capsid resulted in a partial icosahedral ordering of the genome. The residues involved in RNA binding are conserved among all parechoviruses, suggesting an evolutionarily fixed role of the genome in virion assembly. Therefore, putative small molecules disrupting HPeV RNA-capsid protein interactions could be developed into antiviral inhibitors.
(2) Aichi virus 1 (AiV-1) causes diarrhea, abdominal pain, nausea, vomiting, and fever. AiV-1 is identified in environmental screening studies with higher frequency and greater abundance than other human enteric viruses. Accordingly, 80-95% of adults worldwide have suffered from AiV-1 infections. Based on the AiV-1 virion structure, we show that antiviral compounds that were developed against related enteroviruses are unlikely to be effective against AiV-1. We also determined that AiV-1 genome release requires large and reversible reorganization of the capsid.
(3) Saffold virus 3 (Safv-3) causes diseases ranging from gastrointestinal disorders to meningitis. We show that before the Safv-3 genome is released, its particle expands, and holes form in the previously compact capsid. These holes serve as channels for the release of the genome and small capsid proteins VP4 that facilitate subsequent transport of the virus genome into the cell cytoplasm.
Most of economically important honeybee viruses belong to the order Picornavirales and specifically to families Dicistroviridae and Iflaviridae. We determined the first atomic structures of one representative for each of the families: slow bee paralysis virus (SBPV) from the family Iflaviridae and Israeli acute bee paralysis virus (IAPV) from the family Dicistroviridae. Both viruses exhibit unique features not observed in other viruses previously. Capsid protein VP3 of SBPV, the first structurally characterized Iflavirus, has a large C-terminal domain. Five of these domains form “crowns” on virion surface located around icosahedral fivefold symmetry axes. The crown domains are conserved among iflaviruses, however, they have not been observed in any other virus from the order Picornavirales. Unlike many picornaviruses neither IAPV nor SBPV contain a hydrophobic pocket in capsid protein VP1. Therefore, capsid-binding antiviral compounds that were developed against picornaviruses cannot be used to treat honeybee virus infections.

Contact

Veronika Papouskova, (Research project manager)
Tel.: +420549492523
E-mail
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