Avian influenza adapts to humans by acquiring multivalency

Avian influenza viruses represent a recurring threat to human health. In particular highly pathogenic zoonotic avian strains, such as the currently circulating H5N1 subtype, can adapt to infect humans with high mortality, posing a catastrophic pandemic threat, in addition to global decimation of wild and domestic bird populations.

Host adaptation is necessary for efficient replication and sustained human-human transmission. Amongst other adaptations, replication in human cells requires mutations on the surface of the viral polymerase - the machine responsible for creating new copies of its genetic material. These mutations, located in the terminal domains of one of the subunits of the polymerase (PB2) are known to compensate differences in a host protein, ANP32A, that the virus somehow exploits in the infected cell and that is required for replication. This protein has a long disordered tail, that is 30% longer in birds than in humans, and highly negatively charged, comprising around 70% of acidic amino acids. Researchers at the IBS used NMR spectroscopy to reveal the molecular origin of this adaptation.

They demonstrated that while avian ANP32A colocalizes two viral proteins, the polymerase domain PB2, and the nucleoprotein (NP) via two separate interaction sites on its disordered tail, an interaction that could position copies of NP in close proximity to the newly synthesized RNA, they also noticed however that this mechanism would not be possible in human cells, because the disordered tail is too short to accommodate two separate interaction sites. They then demonstrated that the mutations present in the viral polymerase provide a new, multivalent interaction mechanism that allows both viral proteins to simultaneously bind exactly the same stretch of the disordered tail of human ANP32A, forming a dynamic ternary complex via highly dynamic and electrostatic interactions, rapidly, and multivalently, fluctuating between positively charged surfaces on the two viral proteins.

This remarkable piece of molecular engineering on the part of influenza virus underlines the mechanistic plasticity of the infectious agent to overcome species barriers and achieve zoonosis, but also reveals completely new avenues for the development of potent inhibitory strategies against the ever-present pandemic threat of avian influenza.

Multivalent Dynamic Colocalization of Avian Influenza Polymerase and Nucleoprotein by Intrinsically Disordered ANP32A Reveals the Molecular Basis of Human Adaptation. Camacho-Zarco AR, Yu L, Krischuns T, Dedeoglu S, Maurin D, Bouvignies G, Crépin T, Ruigrok RWH, Cusack S, Naffakh N, Blackledge M. Journal of the American Chemical Society 2023 ; 145(38):20985-21001

Contact : Martin Blackledge (IBS/Protein Dynamics and Flexibility by NMR Group)