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Molecular insight into the transmission of avian influenza to enable human infection

​Researchers at CEA-IRIG have used NMR to reveal the molecular mechanisms that support the adaptation of avian influenza virus from birds to humans. By uncovering the secrets of the interactions between the mutated viral polymerase and a key transcription factor in host cells, this new insight will make it possible to study the mechanism of cross-species contagion of these viruses and thus open up potential new therapeutic avenues.

Published on 29 July 2020

Reference :  Molecular basis of host-adaptation interactions between influenza virus polymerase PB2 subunit and ANP32A, Nature Communications

In birds, the avian influenza virus acts via the interaction of its polymerase with a key transcription factor: ANP32A. Two regions of these highly dynamic molecules seemed to be strongly implicated, but the molecular basis of the interaction remained unknown, preventing researchers from understanding how certain mutations in the viral polymerase enabled it to adapt from bird to human and thus acquire a capacity for cross-species contagion. These highly dynamic, so-called intrinsically disordered molecular regions do not form unique structures, nor do they crystallize, complicating their study.

Using NMR, researchers at the Institut de Biologie Structurale CEA-CNRS-UGA have succeeded in deciphering these mechanisms: in birds, the so-called "627-NLS domain" of the viral polymerase binds to a specific area, involving a unique sequence, of the transcription factor ANP32A. However, this sequence does not exist in the human version of the transcription factor - the viral polymerase therefore needs to develop an alternative strategy for binding the transcription factor if it is to successfully infect humans. The virus continually changes its sequence, modifying individual sites by a process called mutation. A particular mutation in its 627 domain has long been known to enable adaptation, and this study finally provides a molecular explanation for this phenomenon. The researchers at the IBS show how this mutation, that forms a complete positively charged surface, allows the polymerase to interact with human ANP32A, in the form of less specific but more numerous, weaker interactions.

This study provides a molecular framework for understanding the differential binding modes underlying the restriction of influenza polymerase by ANP32A in certain species and will allow the identification of new targets for influenza inhibition.

Interdisciplinary Research Institute of Grenoble (IRIG - CEA/CNRS/Université Grenoble Alpes)
European Molecular Biology Laboratory (EMBL) in Grenoble

Influenza A virus
is responsible for 3-5 million severe cases every year, resulting in 250 to 500 000 deaths. Most influenza strains evolve exclusively in the large reservoir of water birds, but some highly pathogenic avian strains (e.g. H5N1, H5N8, H7N9) can infect humans with lethal consequences (up to 60% mortality) and remain pandemic threats for humanity if they develop human-to-human transmissability.

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