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.