CE11 - Caractérisation des structures et relations structure-fonction des macro-molécules biologiques

Structural studies of the entry-fusion complex of poxvirus – POXFUSION

Submission summary

The entry of enveloped viruses is achieved by the fusion of viral and cellular membranes, a critical step in infection that provides targets for vaccines and therapeutics. Viral fusion is catalyzed by a specific protein termed fusion protein, which associate with other proteins on the viral surface to form fusion complexes. In this project we propose to study the fusion complexes of poxviruses, a large family of DNA viruses which includes many pathogens. The most renowned poxvirus is variola virus, the causative agent of smallpox, the deadliest human disease to ever exist. Smallpox was eradicated after a worldwide vaccination campaign but concerns persist that it may re-merge accidentally or intentionally as a bio-weapon. This is especially worrisome because vaccination was discontinued in 1980 and we have lost the herd immunity, so the disease could spread rapidly. To this day, apart from vaccination, our current arsenal against smallpox is very limited.

The poxvirus fusion machinery is by far the most complex of all viral fusion machineries. Poxviruses code for a fusion complex formed by 11 membrane proteins plus several additional proteins that regulate the fusogenic activity of the virus and ensure that it takes place at the right time and place. On the viral surface, the fusion complexes cluster together at the poles of virions and only then can induce membrane fusion. Due to their complexity and despite their importance in poxvirus biology, little is known about the structure of this complex, how is organized on the viral surface and the molecular mechanisms that regulate its activity. This project aims to fill these gaps using the latest technologies in electron microscopy and membrane protein biochemistry. We expect that the results obtained in this project will pave the way for the development of broad-spectrum therapies to treat any disease caused by a poxvirus, wherever and whenever they emerge.

Project coordination

PABLO GUARDADO CALVO (Institut Pasteur)

The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.

Partner

IP Institut Pasteur

Help of the ANR 389,740 euros
Beginning and duration of the scientific project: September 2022 - 36 Months

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