A US-Japanese research team announced it had isolated three genes that explain why the 1918 Spanish flu, believed to be the deadliest infectious disease in history, was so lethal.
The pandemic killed between 20 and 50 million people - more than in all of World War I, which ended in November 1918 - and spread around the world.
The genes allowed the virus to reproduce in lung tissue, according to research published in the Proceedings of the National Academy of Sciences.
"Conventional flu viruses replicate mainly in the upper respiratory tract: the mouth, nose and throat," said University of Wisconsin-Madison virologist Yoshihiro Kawaoka, who co-authored the study along with Masato Hatta, also of UW-Madison.
"The 1918 virus replicates in the upper respiratory tract, but also in the lungs," causing primary pneumonia among its victims," Kawaoka said.
"We wanted to know why the 1918 flu caused severe pneumonia," he added.
Autopsies of Spanish flu victims often revealed fluid-filled lungs severely damaged by massive hemorrhaging.
Virologists linked the virus' ability to invade the lungs with its high level of virulence, but the genes that conferred that ability were unknown, the researchers wrote.
The discovery of the three genes and how they help the virus infect the lungs is important because it could provide a way to quickly identify the potential virulence factors in new pandemic strains of influenza, Kawaoka said.
The genes could also lead to a new class of antiviral drugs, which is urgently needed as vaccines are unlikely to be produced fast enough at the outset of a pandemic to blunt its spread, he added.
The researchers generated Spanish flu viruses from genetic material extracted from preserved lung tissue of three of the pandemic's victims, thanks to Jeffrey Taubenberger's work at the Armed Forces Institute of Pathology.
Taubenberger was able to isolate the eight genes of the 1918 virus by the technique of inverse genetics.
Kawaoka's team blended genetic elements from the 1918 flu virus with those of current flu pathogens, generating viruses that carried different genetical combinations.
Tested on ferrets and mice, most of the combined viruses infected the upper respiratory tract of the laboratory animals but did not cause pneumonia.
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, a protein necessary for the virus to reproduce.
The other key gene makes hemagglutinin, a protein found on the surface of the virus and that confers on viral particles the ability to attach to host cells.
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, Kawaoka said.
Other co-authors of the study include Shinji Watanabe, Jin Hyun Kim and Masato Hatta, also of UW-Madison, and Kyoko Shinya of Kobe University, in Japan.
The work was funded by the Japanese Ministry of Education, Culture, Sports, Science and Technology and by grants-in-aid from the Ministry of Health, Labor and Welfare of Japan.