An experiment to reconstruct the deadly 1918 flu virus has given a new insight into how the infection took hold.
The 1918 virus left young adults worst hit
Scientists discovered a severe immune system reaction was triggered when mice were infected with the recreated virus.
The US team believes the extreme immune response could have provoked the body to begin killing its own cells, making the flu even deadlier.
The study, published in Nature, may aid the hunt for new treatments. The 1918 pandemic took about 50 million lives.
The devastating infection, which is thought to have originated in birds, left young adults worst hit.
Scientists in the US have reconstructed the H1N1 virus in a bid to better understand how it became such an effective killer - and to also bolster knowledge in the face of the current H5N1 bird flu threat.
The researchers infected mice with the recreated influenza virus.
Through functional genomic analysis, they discovered that the mice's immune systems responded fiercely to the infection and remained active until the animals' deaths several days later.
At the same time, the animals also suffered the severe lung disease that is characteristic of the virus.
Dr John Kash, lead author of the study and assistant professor of microbiology at the University of Washington, said: "What we think is happening is that the host's inflammatory response is being highly activated by the virus, and that response is making the virus much more damaging to the host.
"The host's immune system may be overreacting and killing off too many cells, and that may be a key contributor to what makes this virus more pathogenic."
Dr Christopher Basler, a co-author from Mount Sinai School of Medicine, New York, said: "Our next step is to repeat these experiments, but deconstruct what the immune system is doing so that we can understand why it is reacting so strongly, yet failing to fight the infection."
The researchers said understanding how the virus worked would help in the fight against influenza.
Dr Basler said: "This could help us develop more targeted therapies to combat pathogenic infections, including different types of influenzas or perhaps avian influenza."
Paul Hunter, professor of health protection from the University of East Anglia, UK, said: "People who have died from the current form of bird flu have died in the same sort of fashion as the people who died during the 1918 pandemic. It is an extraordinarily unpleasant death.
"Clearly, the difference between the virus now and the one around in 1918 is that the current one has yet to develop the ability to spread swiftly from person to person.
"It is very important to study the 1918 flu to understand the current avian flu virus."