Avian influenza A, more known as bird flu, has existed for 25 years. Despite its long existence, it wasn’t considered a significant public health threat because it was limited to avians. 

However, this year, dairy cows in the US had unexpectedly begun getting infected by an avian H5N1 strain. Worse, workers exposed to infected cows and poultry reportedly experienced mild symptoms. While bird flu cannot be transmitted between humans yet, experts fear that such is not far from happening. 

The Cusack group at EMBL Grenoble was among the first to study the replication process of these viruses. In their study published in Nature Communications, the group presents the various mutations the avian influenza virus can potentially undergo to replicate successfully in cells of mammals, including humans.

Results show that ANP32, a host cell protein, connects two viral polymerases, forming the replication complex. Replicase, one of the two polymerases, creates copies of the viral RNA, while encapsidase packages the copy inside a protective coating. 

Keeping the stability of these two polymerases is the primary function of ANP32’s long tail. This very tail prevents the avian influenza virus from quickly infecting mammals since the ANP32 tails differ between birds and mammals. 

Benoît Arragain, a postdoctoral fellow in the Cusack group and the study’s first author, said:

    “The key difference between avian and human ANP32 is a 33-amino-acid insertion in the avian tail, and the polymerase has to adapt to this     difference. For the avian-adapted polymerase to replicate in human cells, it must acquire certain mutations to be able to use human ANP32.”

He and his fellow researchers conducted in vitro experiments with the H7N9 strain and determined the amino acids critical to forming the replication complex. They also identified the mutations required for the avian influenza polymerase to adapt to mammalian cells. 

Arragain added:

    “We also collaborated with the Naffakh group at the Institut Pasteur, who carried out cellular experiments,” added Arragain. “In addition, we     obtained the structure of the human type B influenza replication complex, which is similar to that of influenza A. The cellular experiments     confirmed our structural data.”

With these insights from this study, researchers can explore polymerase mutations in other strains and discover long-term solutions by developing anti-influenza drugs. 

Stephen Cusack, EMBL Grenoble Senior Scientist, said they plan to study how the replication complex dynamically performs replication. 

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