How does bird flu manage to infect mammal species?

In recent years, significant strides have been made in reducing the impact of seasonal flu epidemics through public health measures, surveillance, and vaccination efforts targeting human influenza viruses A and B. However, the potential outbreak of avian influenza A, commonly known as bird flu, in mammal species – including humans – poses a substantial public health threat.

Mutations help bird flu cross species barriers

The Cusack group at EMBL Grenoble has been focusing on the replication processes of influenza viruses, and their latest study sheds light on the mutations that allow the avian influenza virus to replicate within mammalian cells.

Certain strains of avian influenza can cause severe disease and mortality, but key biological differences between birds and mammals usually prevent these viruses from spreading to other species. 

How does bird flu infect mammal species?

To infect mammals, the avian influenza virus must overcome two primary barriers: it must gain the ability to enter mammalian cells and replicate within them. To trigger an epidemic or pandemic, the virus must also evolve to transmit effectively between humans.

Unfortunately, incidents of avian influenza infecting wild and domestic mammals are becoming increasingly common. A particularly concerning development is the recent infection of dairy cows in the United States by an avian H5N1 strain, which risks becoming endemic in cattle. 

This development could facilitate the virus’s adaptation to humans, with a few cases of human transmission already reported, though these have so far resulted in only mild symptoms.

Enzyme responsible for virus replication 

Central to this process is the viral polymerase, an enzyme responsible for the virus’s replication within host cells. This versatile protein can rearrange itself to perform various functions during the infection process, including transcription – where viral RNA is copied into messenger RNA to produce viral proteins – and replication, where copies of the viral RNA are created to package into new viruses.

Studying viral replication is challenging because it involves two viral polymerases and a host cell protein called ANP32. These three proteins form the replication complex, a molecular machine essential for replication. 

ANP32 acts as a stabilizer for certain cellular proteins, thanks to its long acidic tail. Although ANP32’s critical role in influenza virus replication was identified in 2015, its precise function remained unclear until now.

Polymerases perform distinct functions 

The new study, published in Nature Communications, reveals that ANP32 serves as a bridge between the two viral polymerases – replicase and encapsidase. These polymerases take on different conformations to perform distinct functions: replicase is involved in creating copies of viral RNA, while encapsidase helps package these copies into a protective coating, with the aid of ANP32.

ANP32’s tail plays a crucial role in stabilizing the replication complex, enabling its formation within the host cell. Interestingly, while the core of the ANP32 protein is similar in birds and mammals, the tail differs significantly. This difference explains why avian influenza viruses struggle to replicate in mammals and humans.

“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,” explained Benoît Arragain, a postdoctoral fellow in the Cusack group and first author of the study. 

“For the avian-adapted polymerase to replicate in human cells, it must acquire certain mutations to be able to use human ANP32.”

Insights into the influenza replication complex

To delve deeper into this process, Arragain and his collaborators obtained the structure of the replicase and encapsidase conformations of a human-adapted avian influenza polymerase from the H7N9 strain while interacting with human ANP32. 

This structural information pinpoints the amino acids crucial for forming the replication complex and identifies the mutations that could allow avian influenza polymerase to adapt to mammalian cells.

These findings were made possible through in vitro experiments conducted at EMBL Grenoble, utilizing the Eukaryotic Expression Facility, the ISBG biophysical platform, and the cryo-electron microscopy platform via the Partnership for Structural Biology. 

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

These new insights into the influenza replication complex are valuable for studying polymerase mutations in other similar avian influenza strains. The structure obtained from the H7N9 strain can be adapted to study other strains such as H5N1.

Broader implications of the study 

“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,” said Stephen Cusack, EMBL Grenoble Senior Scientist and study leader, who has been studying influenza viruses for 30 years. 

“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.”

These findings are also significant for the long-term development of anti-influenza drugs, as there are currently no existing drugs that specifically target the replication complex. 

“But it’s just the beginning. 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,” Cusack concluded.  

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