WIKIMEDIA, GAVIN SCHAEFERThe avian influenza virus H9N2, which helped give rise to the deadly H7N9, evolved to become increasingly infectious in chickens in the years leading up to H7N9’s emergence, according to a paper published yesterday (December 29) in PNAS. H9N2 has been circulating on chicken farms in China since 1994. In recent years, the virus recombined in poultry markets with H7 and N9 viruses that had been passed from wild birds to domestic ducks. The resulting H7N9 flu virus jumped to humans in 2013, and by October 2014 had killed 175 of the 453 people it had infected, according to the World Health Organization. This latest viral analysis sheds light on the genetic changes to H9N2 that may have made H7N9’s emergence possible.

“[The] study reveals the increased H9N2 prevalence in poultry farms in China, due to the emergence of a more infectious and antigenically distinct...

“With the combination of vaccine-driven selection and reassortment going on, you got the precursor of the H9N2 that was optimal for complementing H7N9 and going into humans,” said study coauthor Robert Webster of St. Jude Children’s Research Hospital in Memphis, Tennessee.

Webster and his colleagues collaborated with the lab of Jinhua Liu at China Agricultural University in Beijing, which had access to samples of H9N2 isolated periodically from infected chickens since the virus was first identified in south China.

The researchers compared the genetic sequences of the viruses obtained over time. Beginning in 2009, the diversity of circulating viruses decreased. “Reduced genetic diversity basically means one thing is more successful than any other,” explained John McCauley of the MRC National Institute for Medical Research in London, who was not involved in the study.

The precipitous drop in diversity suggested to the researchers that they should search for the emergence of a particularly fit H9N2 subtype that might have spread rapidly through the chicken population. Indeed, when they made phylogenetic trees of their isolated viruses from different eras, the researchers found that almost all of the viruses isolated in 2010 through 2013 formed a single clade, called G57. The G57 viral subtype had gradually evolved through reassortment with other bird viruses and through gradual drift of its genetic sequence, reaching its current form in 2007.

To understand why G57 had become so dominant, the researchers next inoculated live chickens with various viral subtypes. They found that the G57 viruses  reached higher levels than other H9N2 subtypes within the inoculated chickens and spread more readily between chickens.

Additionally, the researchers showed that G57 viruses are more resistant to H9N2 vaccines than are similar viruses because of changes in the external proteins that vaccines prime the immune system to recognize. Chickens in China have received the H9N2 vaccine since 1998, but its efficacy began to decline in 2007.

Finally, the researchers compared the sequences of H7N9 viruses to their H9N2 sequences, finding that H7N9 took all six of its internal protein-coding genes from G57 viruses.

Webster pointed out that H9N2 has also reassorted with the bird flu virus H5N1 in recent history, increasing the threat of H5N1 to human health. Last FebruaryLast , a Chinese woman died from a novel H10N8 flu virus that had reassorted with H9N2.

“What exactly does H9N2 contribute to these viruses to make them fitter, and so pathogenic for humans?” asked Webster. “That is an unanswered question for the future.”

However, McCauley said there is much left to learn about the G57 strain. It is possible that other H9N2 strains could have given rise to H7N9 and that G57 simply became dominant in the right place at the right time.

Still, McCauley said that it is wise for public health agencies worldwide to pay attention to H9N2, which is prevalent not only in China but across Asia and the Middle East. “It’s studies like this that really go into this in such detail that are required elsewhere,” he said.

Public health workers should be particularly vigilant for novel viruses that have reassorted with the G57 version of H9N2, said Webster. “Knowing the genomic sequence of G57, you can be on the lookout for viruses that cause problems.”

J. Pu et al., “Evolution of the H9N2 influenza genotype that facilitated the genesis of the novel H7N9 virus,” PNAS, doi:10.1073/pnas.1422456112, 2014.

Correction (January 2): This article has been update to correct a typo in the second paragraph.

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