Findings reported in PNAS implicate the viral RNA polymerase complex as a major determinant of pathogenicity.
Researchers have identified a set of three genes that enhanced the virulence of the 1918 Spanish flu virus. These genes gave the virus the capacity to reproduce in lung tissue; conventional flu viruses replicate in the upper respiratory tract.
“The 1918 virus replicates in the upper respiratory tract but also in the lungs,” notes Yoshihiro Kawaoka, Ph.D., professor of pathobiological sciences in the University of Wisconsin-Madison School of Veterinary Medicine. “We wanted to know why the 1918 flu caused severe pneumonia.”
To find the gene or genes that enabled the virus to invade the lungs, Dr. Kawaoka’s group blended genetic elements from the 1918 flu virus with those of a currently circulating avian influenza virus and tested the variants on ferrets.
Substituting single genes from the 1918 virus onto the template of a much more benign contemporary virus called K173 yielded, for the most part, agents that could only replicate in the upper respiratory tract. One exception, however, included a complex of three genes that, acting in concert with another key gene, allowed the virus to efficiently colonize lung cells and make RNA polymerase, the scientists state.
“The RNA polymerase is used to make new copies of the virus,” Dr. Kawaoka explains. Without the protein, the virus is unable to make new virus particles and spread infection to nearby cells.
In the late 1990s, scientists were able to recover genes from the 1918 virus by looking in the preserved lung tissue of some of the pandemic’s victims. Using the relic genes, Dr. Kawaoka’s group was able to generate viruses that carry different combinations of the 1918 virus and modern seasonal influenza virus.
When tested, most of the hybrid viruses only infected the nasal passages of ferrets and didn’t cause pneumonia. But one did infect the lungs and it carried the RNA polymerase genes from the 1918 virus that allowed the virus to synthesize its proteins.
In 2004, Dr. Kawaoka and his team identified another key gene from the 1918 virus that enhanced the pathogen’s virulence in mice. That gene makes hemagglutinin, a protein found on the surface of the virus that confers on viral particles the ability to attach to host cells.
“Here, I think we are talking about another mechanism,” Dr. Kawaoka says. The RNA polymerase is used to make copies of the virus once it has entered a host cell. The role of hemagglutinin is to help the virus gain access to cells.
Results of the current study are published in Proceedings of the National Academy of Sciences.
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