An international team of scientists has created a highly pathogenic laboratory hybrid of the H5N1 bird flu and human seasonal flu viruses by swapping just one gene, and propose that a similar genetic interaction could happen in nature between the current pandemic H1N1 swine flu and H5N1 avian flu strains, highlighting the importance of continued surveillance.

A report of the study by senior author is Dr Yoshihiro Kawaoka, professor of pathobiological sciences in the School of Veterinary Medicine at the University of Wisconsin-Madison in the US, and colleagues, appeared online before print on 22 February in the Proceedings of the National Academy of Sciences, PNAS.

Based on reported statistics, once it infects humans, the H5N1 bird flu virus kills humans at a much higher rate than the H1N1 swine flu virus circulating amongst us in the current global pandemic. According to the World Health Organization (WHO), as of 21 December 2009, H5N1 had spread worldwide among bird populations and caused 447 confirmed human cases and 263 deaths.

When two different virus strains infect the same host, they often exchange genes, a process known as reassortment. A significant number of experts are concerned that as H5N1 spreads more widely and infects more people, it will come across more hosts who are also carrying human seasonal flu viruses. This increases the likelihood of a new strain emerging that has the severity of the bird flu virus and the infection rate of the swine flu virus, leading to a new global pandemic with much deadlier consequences than the one we are experiencing at the moment.

To evaluate the potential of such a scenario, using laboratory mice and “reverse genetics”, Kawaoka and colleagues experimented with creating 254 combinations of reassortant viruses of avian H5N1 and human H3N2 influenza viruses, both of which are currently circulating among the same populations.

Unlike previous studies that found lab hybrids had always been less virulent than parent strains, the researchers in this study found some hybrids were more pathogenic than the original H5N1 virus.

In one case in particular, where they introduced a single gene segment from human H3N2 seasonal flu virus into avian H5N1, it produced a highly pathogenic form of bird flu.

Kawaoka said the study raised fresh concerns about the emergence of a highly virulent and contagious strain of avian flu:

“H5N1 virus has never acquired the ability to transmit among humans, which is why we haven’t had a pandemic. The worry is that the pandemic H1N1 virus may provide that nature in the background of this highly pathogenic H5N1 virus,” he said

Kawaoka suggested that because of the swine flu pandemic people have sort of forgotten about H5N1 avian flu.

“But the reality is that H5N1 avian virus is still out there,” he said, adding that:

“Our data suggests that it is possible there may be reassortment between H5 and pandemic H1N1 that can create a more pathogenic H5N1 virus.”

He and his colleagues tested the pathogenicity of 75 reassortant H5 viruses in mice and found that 22 were more pathogenic than the parental virus, and three were “extremely virulent”.

The increased virulence appears to come from a gene segment called PB2, which is known to affect how well the bird flu virus grows in human and other mammals. The authors wrote that:

“We found that the presence of Tok07 PB2 protein in the ribonucleoprotein (RNP) complex allowed efficient viral RNA transcription in a minigenome assay and that RNP activity played an essential role in the viability and replicative ability of the reassortant viruses.”

They concluded that these results suggest:

“Reassortment between an avian H5N1 virus with low pathogenicity in mice and a human virus could result in highly pathogenic viruses and that the human virus PB2 segment functions in the background of an avian H5N1 virus, enhancing its virulence.”

The researchers said it was very important to continue surveillance and monitoring all situations where it might be possible for avian and human flu viruses to interact and create new highly pathogenic reassortant viruses. The discovery of the PB2 gene segement as a possible enhancer of virulence could be very helpful should a pandemic strain emerge.

The study was supported by grants from the US National Institutes of Health, the Japan Society for the Promotion of Science, the Ministry of Education, Culture, Sports, Science and Technology of Japan, and the Japan Science and Technology Agency.

“Reassortment between avian H5N1 and human H3N2 influenza viruses creates hybrid viruses with substantial virulence.”

Chengjun Li, Masato Hatta, Chairul A. Nidom, Yukiko Muramoto, Shinji Watanabe, Gabriele Neumann, and Yoshihiro Kawaoka.

PNAS, published online before print 22 February 2010

DOI:10.1073/pnas.0912807107

Source: University of Wisconsin-Madison.

Written by: Catharine Paddock, PhD