H5N1 virus may be adapting to pigs in Indonesia

Mar 31, 2009 (CIDRAP News) – Scientists report that H5N1 avian influenza viruses may be adapting to pigs, as evidenced by the finding that H5N1 viruses isolated from pigs in Indonesia were less harmful to mice than were H5N1 viruses from chickens.

The finding suggests that in growing in pigs, the virus may have become less harmful to mammals in general, the authors report. That sounds reassuring, but the authors say it may mean the virus is one step closer to turning into a human pandemic strain.

In the study, scientists from Japan and Indonesia collected viruses from chickens and pigs in Indonesia, grew them in laboratory cell cultures, and used them to infect mice. They found that the viruses from pigs were less lethal to mice than the viruses from chickens, according to their recent report in the Archives of Virology.

"We found that swine isolates were less virulent to mice than avian isolates, suggesting that the viruses became attenuated during their replication in pigs," the report states.

An intermediate host
Pigs are seen as a possible intermediate host that can help avian flu viruses adapt to humans, because the epithelial cells in pigs' trachea can be infected by both avian and human flu viruses, the article notes. If avian and human viruses infected a pig at the same time, they could mix or reassort, giving rise to a novel strain that might be able to spread in humans. The flu pandemics of 1957-58 and 1968-69 were caused by avian-human hybrid viruses, though it is not known if they arose in pigs.

But even if they don't mix with human strains, avian flu viruses that infect pigs are believed capable of adapting to them—gaining the capability to grow efficiently in swine cells—and thereby adapting to other mammals, the authors write. Humans occasionally are infected with swine flu viruses, something that has been reported at least twice this flu season in the United States, according to the Centers for Disease Control and Prevention.

So far, H5N1 infections in pigs have been reported rarely or gone unnoticed because infected pigs show no signs of illness, the scientists write. But the authors, who include Chairul Nidom of Airlangga University in Surabaya, Indonesia, report that they found H5N1 infections in pigs in Indonesia in 2005, 2006, and 2007. They determined that the swine viruses were closely related to viruses in chickens found nearby, indicating H5N1 spread from chickens to pigs at least three different times.

They gathered three viruses from pigs and two from chickens on East Java in 2006 and 2007. They first determined that all the viruses grew well in embryonated eggs and in cultures of canine kidney cells, demonstrating that both avian and swine strains could grow in mammalian cell cultures. They then infected groups of mice with a range of doses of the five isolates.

The results showed that all three pig viruses were less virulent in mice than the chicken viruses were, as measured by how large a dose it took to kill half of the mice. Two of the pig isolates were "strongly attenuated" in mice.

In a genetic analysis, the scientists found several amino acid differences that might explain the lower virulence of the swine isolates, but they "were unable to determine which mutations were strongly correlated to low virulence in mice because these mutations are frequently found among avian and human H5N1 viruses," the report says.

Prelude to a pandemic strain?
The authors offer this interpretation of their findings: "Since our swine strains were isolated from pigs with no apparent influenza-like symptoms, the decrease of pathogenicity in mice suggests that the H5N1 viruses may have lost their pathogenicity in mammals during replication in pigs. Given that for the H5N1 viruses to cause a pandemic, they would likely become attenuated in humans, becoming attenuated in mammals may be a prelude to the generation of a pandemic strain."

They add that because H5N1 infections in swine increase the risk that a pandemic strain could emerge, the findings point up the need for "continuous surveillance and management of H5N1 viruses in pigs."

The findings may mean that H5N1 viruses from swine will be less virulent in mammals generally, but it's not clear that the viruses have truly adapted to swine, said Richard Webby, PhD, a virologist, flu researcher, and associate member of the Department of Infectious Diseases at St. Jude Children's Research Hospital in Memphis.

Noting that the study authors used only five isolates, Webby said, "Trying to make too much of a conclusion from that number would be premature. The two least lethal viruses were both from swine, but one [swine isolate] was lethal. So perhaps if these become adapted to mammals, they're potentially going to be less pathogenic."

Whether H5N1 viruses become more or less virulent when they adapt to mammals is a very important question, he said, adding that the findings "might be to some extent reassuring."

Regarding the authors' statement that attenuation of the virus in mammals might be a prelude to the development of a pandemic strain, Webby commented, "I guess the thought behind that is that for a pathogen to be successful, it's got to transmit readily, so if it makes the host too sick, so they go to a hospital or die, the chances of its transmitting to someone else are reduced."

But Webby told CIDRAP News that it's not clear that H5N1 viruses have really become established in swine anywhere. "If these viruses have gone into swine, I think the key is whether they become established in swine. If that happened, we'd be concerned. I think the consensus now is that pigs are like humans; they can be infected, but it's unlikely there'd be a lot of transmission."

He said US Department of Agriculture researchers have infected pigs with H5N1 viruses and found that the viruses didn't grow at all. But those researchers used viruses that didn't come from pigs in the first place. He noted that pigs often are fed broken eggs or even chicken carcasses, and such pigs might carry the virus in their snouts without becoming truly infected.

Webby suggested that researchers now should "put these swine viruses back into swine and see if they actually are more adapted to swine than the avian viruses."

Takano R, Nidom CA, Kiso M, et al. A comparison of the pathogenicity of avian and swine H5N1 infuenza viruses in Indonesia. Arch Virol 2009 (early online publication Mar 14) [Abstract]

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