The 2009 H1N1 influenza virus used a new strategy to cross from birds into humans, a warning that it has more than one trick up its sleeve to jump the species barrier and become virulent.
In a report in this week's early online edition of the journal Proceedings of the National Academy of Sciences, University of California, Berkeley, researchers show that the H1N1, or swine flu, virus adopted a new mutation in one of its genes distinct from the mutations found in previous flu viruses, including those responsible for the Spanish influenza pandemic of 1918, the "Asian" flu pandemic in 1957 and the "Hong Kong" pandemic of 1968.
Previous influenza strains that crossed from birds into people had a specific point mutation in the bird virus's polymerase gene that allowed the protein to operate efficiently inside humans as well. The polymerase transcribes the virus's RNA, allowing the host to express viral genes, and also copies the viral genome, needed to make new viruses.
The 2009 H1N1 virus retains the bird version of the polymerase, but has a second mutation that seems to suppress the ability of human cells to prevent the bird polymerase from working.
"We were quite shocked when we looked at the swine flu virus, which was clearly replicating in people and other mammalian systems, yet had a polymerase that looked like it was derived from a bird virus, which should not function too well in a human cell type," said UC Berkeley post-doctoral fellow Andrew Mehle of the Department of Molecular and Cell Biology. "The other mutation within the polymerase seems to compensate and allow the enzyme to function."
The researchers also discovered another strategy - one not yet adopted by any known flu virus - by which influenza virus can increase its virulence even more. When a particular human subunit is substituted for one of the three protein subunits that make up the bird polymerase, the new combination makes the polymerase more efficient in human cells.
"This is an extremely rare mutation and a rare combination, which suggests that there may be other ways that haven't emerged yet that these viruses are going to continue to evolve," said Jennifer Doudna, UC Berkeley professor of molecular and cell biology and an investigator in the Howard Hughes Medical Institute.
"As mechanistic biologists, we are hoping that by understanding how the virus works at the molecular level, we will be able to predict with more accuracy how it will evolve."
She suggested that those monitoring influenza outbreaks around the world in search of new variants be on the lookout for this recombination of polymerase subunits, which could herald an uptick in swine flu virulence. The findings also could help scientists develop better antiviral treatments, Mehle and Doudna said.
"The more we can understand the biochemistry and the particular structure of these polymerase complexes, the better we can make rational decisions about drug development," Mehle said.
H1N1, which appeared on the scene earlier this year, was dubbed swine flu because it emerged from pigs, in which human, bird and pig influenza viruses mixed, swapped genes and gave rise to a variant that could infect human cells and reproduce.
While mutations in the surface protein hemagglutinin - indicated by the H in H1N1 - are key to allowing the virus to enter human cells, mutations in the polymerase enzyme are key to the virus's ability to replicate inside human cells. All previous flu strains that entered and were transmitted in humans had a single mutation in the second subunit of the bird polymerase gene, which apparently allowed the enzyme to operate in human cells.