Project description
Unmasking virus influenza interactions with human proteins
Avian influenza, commonly known as bird flu, is caused by different strains of the influenza A virus and primarily affects birds. However, mutations in a key viral enzyme enable the virus to infect human cells through interaction with specific human proteins. Funded by the Marie Skłodowska-Curie Actions programme, the AvINFLUENZA project aims to investigate the interaction between the mutated viral protein and human proteins, as well as characterise the dynamics of this interaction. Project findings will offer fundamental insight into the process of viral replication and contribute to the development of new antiviral drugs to address the potential pandemic threat posed by avian influenza.
Objective
Due to its high prevalence among birds and high human fatality rate, avian influenza represents a serious and continuing pandemic threat, in particular via mutations that facilitate human infection, resulting in pathogenic strains. Mutations associated with human infection are concentrated in the PB2 subunit of influenza polymerase. This subunit is imported into the nucleus, where viral replication and transcription occurs, via a selective interaction with host importin-alpha proteins. Once in the nucleus, interaction of PB2 with another host protein called ANP32A, has been proposed to play an essential species-specific regulatory role.
The behavior of PB2 in solution reveals a high level of conformational flexibility that is essential to function. In addition, intrinsically disordered domains of both ANP32A and importin-alpha are thought to play important roles in the interaction with PB2. This uncommonly high level of disorder presents particular challenges for standard structural studies.
This project aims to characterize structurally two protein-protein interactions of the human-adapted PB2 subunit of influenza polymerase with these two human proteins:
1. Importin-alpha
2. ANP32A
Highly dynamic complexes such as the targets of this proposal lie outside of the scope of standard methods of structural biology, and are therefore often not described. The high level of flexibility of these systems requires an innovative and integrative structural approach that will combine paramagnetic NMR with techniques such as ensemble methods to describe the conformational equilibria of highly dynamic systems, NMR relaxation dispersion and CEST, SAXS and single-molecule FRET.
Through the structural and dynamic characterization of these interactions between human-adapted avian influenza polymerase and two human host proteins, we will contribute to a deeper understanding of viral replication, providing the basic information to facilitate the design of innovative drugs.
Fields of science (EuroSciVoc)
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques.
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques.
- natural sciencesbiological sciencesbiochemistrybiomoleculesproteinsproteomics
- medical and health scienceshealth sciencespublic healthepidemiologypandemics
- medical and health scienceshealth sciencesinfectious diseasesRNA virusesinfluenza
- natural sciencesbiological sciencesgeneticsmutation
- natural sciencesbiological sciencesmolecular biologystructural biology
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Programme(s)
Funding Scheme
MSCA-IF-EF-ST - Standard EFCoordinator
75794 Paris
France