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How Avian Flu Infects Humans

05/02/2013
Rachael Moeller Gorman

Two new papers illuminate how avian influenza viruses can infect humans. Learn more...


With the emerging threat of the H7N9 avian influenza virus, which has killed about 20% of humans who have contracted it from poultry in China since late March, fears of avian flu becoming transmissible from human to human are on the rise again.

The interaction between a mutated H5 HA protein and a human receptor analog, in the cis conformation. Source: Science




Two new papers published today in Science examine just how that could happen (1-2). In one study, researchers used X-ray crystallography to visualize at the atomic level how mutations change the strength of the H5N1 avian flu virus’s attachment to human respiratory cells. In the second study, another team created H5N1/H1N1 hybrid viruses that were more easily transmitted between mammals.

“This tells us what kind of mutation we are looking for in future surveillance,” said George Gao, a structural virologist at the Chinese Academy of Sciences in Beijing and co-author of the X-ray crystallography paper. “It can help for the pandemic prediction.”

In their paper, Gao and colleagues looked at the connection between virus and host. Recently, researchers in the Netherlands mutated H5N1 viruses to be easily transmissible via respiratory particles from one ferret to another. The mutations occurred in the viral gene that encodes for hemagglutinin (HA), a protein that binds to respiratory cell receptors containing sialic acid.

But the molecular mechanisms behind this process were unclear. So Gao and colleagues generated wild-type H5 HA proteins and mutant H5 HA proteins. They then joined each HA protein with either avian sialic acid respiratory receptor analogs or human sialic acid respiratory receptor analogs.

Using X-ray crystallography, the team visualized the complex and found that the HA mutation at Q226L causes a cis/trans conformational switch in the respiratory cell receptor. This switch changes how strongly the influenza virus binds to the respiratory cell. Wild-type HA did not bind human receptor analogs at all, but HA with the Q226L mutation did bind the receptor, which would cause disease in vivo.

The team is currently working on H7N9 virus proteins, whose HA has a natural Q226L substitution. The work may help researchers understand and quell the new influenza outbreak in China.

In the other paper, researchers report that two different strains of avian flu could fuse inside livestock hosts into something even more potent.

“The 2009 H1N1 virus caused the globe pandemic and now co-exists with H5N1 viruses in many areas of the world,” said Hualan Chen at the Animal Influenza Laboratory of the Ministry of Agriculture, Harbin, China and author on the paper. “So we asked: could an H5N1 reassortment between avian H5N1 and the highly transmissible 2009 H1N1 virus become transmissible among mammals and potentially cause a human pandemic?”

Using reverse genetics, Chen’s team used a duck isolate of the H5N1 virus and the H1N1 virus to create 127 reassortment viruses. They tested how deadly these viruses are in mice, as a stand-in for humans, as well as whether the viruses were passed easily between guinea pigs, which possess airway receptors similar to both mammals and birds.

They found two genes that enabled the H5N1 virus to be transferred between guinea pigs through the air: polymerase acidic (PA) and non-structural protein (NS). These genes from the H1N1 virus allowed it to travel via respiratory droplet. In addition, several other influenza genes—notably nucleoprotein (NP), neuraminidase (NA), and matrix (M)—also enabled the virus to spread between mammals more easily.

In the end, Chen said that the paper shows that genetic material from different viruses can mix within livestock hosts to produce viruses with the ability to move between mammals, and potentially between humans.

References

1. Zhang, W., Y. Shi, X. Lu, Y. Shu, J. Qi, G. Gao. 2013. An airborne transmissible avian influenza H5 hemagglutinin seen at the atomic level. Science (published online 05/02/2013).

2. Zhang, Y., Q. Zhang, H. Kong, Y. Jiang, Y. Gao, G. Deng, J. Shi, G. Tian, L. Liu, J. Liu, Y. Guan, Z. Bu, H. Chen. 2013. H5N1 hybrid viruses bearing 2009/H1N1 virus genes transmit in guinea pigs by respiratory droplet. Science (published online 05/02/2013).