AvINFLUENZA · Molecular basis of avian influenza polymerase adaptation to human hosts
Horizon 2020 — Marie Skłodowska-Curie Actions
- Duration
- 2019-07-01 → 2021-06-30
- EU contribution
- €185,076
- Participants
- 1
- Scheme
- MSCA-IF-EF-ST
Lines connect the coordinator with its partners.
Results in brief
Molecular basis of avian influenza polymerase adaptation to human hosts
Influenza A virus (IAV) is responsible for 3–5 million severe cases every year, resulting in 250 000-500,000 deaths. Most influenza strains evolve exclusively in water birds, but some highly pathogenic avian strains (e.g., H5N1, H5N8 and H7N9) can infect humans with lethal consequences (up to 60% mortality) and are potential pandemic threats for humanity if they acquire the ability to transmit from human to human. However, these avian viruses need to acquire mutations in their viral polymerase, the molecule responsible for producing more copies of their genome, in order to adapt and therefore efficiently replicate in humans. Few mutations are required for avian to human adaptation, and in particular mutation of a negative for a positively charged residue (glutamic for lysine) in the position “627” of the polymerase rescues viral replication in human cells. In fact, this mutation was present in the influenza viruses that produced the pandemics of 1918, 1957 and 1968. A few years ago was discovered that this adaptation occurs because there is difference between the avian and the human version of a protein called ANP32a, since the avian protein is 33 residues longer. However, there is no information regarding how the viral polymerase interacts with ANP32a or how does mutation 627 helps an avian virus to adapt to human ANP32a.
Data: CORDIS, © European Union
Project 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-alpha2. ANP32AHighly 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.
Original text from CORDIS.
Participants
- CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE CNRS · ParisCoordinatorFrance
Links
Data: CORDIS, © European Union