How does bird flu cross species barrier to infect mammals?

A new study has identified the enzyme in avian influenza that mutates to allow the virus to replicate in humans.

The structure of the enzyme, ANP32, can now be used to determine the mutations to monitor for in the field. It will also help assess if a strain is adapting to infect and transmit between mammals.

The finding comes as the highly pathogenic H5N1 clade 2.3.4.4b causes widespread disease in birds and mammals, including in marine mammals and US dairy cows.

To infect mammals, avian influenza viruses must acquire the ability to enter and replicate within mammalian cells.

Replication involves a complex of 3 different enzymes – replicase, encapsidase, and ANP32 – which make copies of the viral RNA and packaging it into new virus particles.

ANP32 plays a crucial role by acting as a stabiliser to allow the replication complex to form within the host cell. It is able to do this due to a key structural feature – its long tale of acidic amino acids.

The results of the new study, published in Nature Communications, show that ANP32 acts as a bridge between replicase and encapsidase.

This tail differs between birds and mammals, which explains why avian influenza virus does not replicate easily in mammals and humans.

Instead, replicase and encapsidase must acquire certain mutations to be able to use human ANP32.

The researchers determined the protein structure of human-adapted avian influenza replicase and encapsidase while they were interacting with human ANP32. This provides detailed information about which amino acids are important in forming the replication complex and which mutations could allow it to adapt to mammalian cells.

“The threat of a new pandemic caused by highly pathogenic, human-adapted avian influenza strains with a high mortality rate needs to be taken seriously,” says Stephen Cusack, senior scientist at European Molecular Biology Laboratory Grenoble, who led the research.

“One of the key responses to this threat includes monitoring mutations in the virus in the field. Knowing this structure allows us to interpret these mutations and assess if a strain is on the path of adaptation to infect and transmit between mammals.”

The findings are also useful for influenza drug development, as there aren’t currently any drugs that target the replication complex specifically.

“What we want to do next is to understand how the replication complex works dynamically, in other words, to know in more detail how it actively performs replication,” says Cusack.