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Modelling the influenza viral genome to an unprecedented scale

​Scientists at IRIG have observed, to a resolution of 0.5 nanometres, the interactions between the influenza virus genome and its associated proteins. This opens the way to a better understanding of the mechanisms underlying the replication of this virus with high pandemic potential.​

Published on 30 January 2024

Every year, the influenza virus infects between 2 and 6 million people in France. Other influenza viruses, that are very similar to the human influenza virus, cause epizootics that also threaten the human health, as they can cross the species barrier with new viral forms emerging. In particular, the avian influenza epizootic that has been raging in Europe since October 2021 is affecting domestic and wild birds with unprecedented virulence and contagiousness. Given this situation, the WHO has placed the various influenza virus strains under very close surveillance.

Further upstream, scientists at Irig are seeking to elucidate the molecular mechanisms that enable the influenza virus to mutate or adapt to other species.

The genome of this family of viruses is fragmented in eight single-stranded RNA molecules. Each RNA fragment is covered with multiple copies of the viral nucleoprotein, and both fragment ends interact with a viral RNA polymerase (involved in the virus proliferation). Each of these eight assemblies forms a ribonucleoprotein complex, with an extremely flexible and dynamic architecture. Until now, scientists have extracted ribonucleoprotein complexes directly from viruses in order to observe them by cryo-electron microscopy, but they have been unable to elucidate their detailed structures due to a lack of sufficient material and technical limitations.

Production of analogues in vitro

To circumvent this difficulty, the scientists at Irig chose not to use viral extracts but instead to use their expertise in the expression and purification of viral nucleoproteins produced in vitro (recombinant). They developed a protocol to generate analogues of ribonucleoprotein complexes in vitro by self-assembly of nucleoproteins and small RNA probes. Thanks to this new approach, they were able to produce enough biological material to observe these complexes at high resolution.

Using state-of-the-art equipment and a very large dataset, they were able to reconstruct an initial three-dimensional model at nanometric resolution, which they were then able to refine to a resolution of 0.5 nanometres (10-9 m).

With a high-resolution 3D reconstruction of analogues of influenza ribonucleoprotein complexes, scientists can now describe the interactions between the nucleoproteins within them. These appear to be very similar to those observed in the 3D structures of smaller biological assemblies previously obtained by X-ray diffraction.

More interestingly, the new reconstruction at sub-nanometric resolution reveals for the first time the arrangement of the RNA in the complexes. While the RNA appears to be involved in structuring the ribonucleoprotein complexes, it also appears to slide freely across the surface of the proteins, most likely to facilitate access to the RNA polymerase and thus enable replication of the virus.

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