Spanish flu, bird flu and the innate immune response

One of the great mysteries for both historians and scientists surrounding the 1918 influenza pandemic, which killed almost 50 million people, was why it affected so many young and healthy adults as well as the very old and very young.

Studies of the 1918 flu in comparison to conventional influenza viruses in mice have shown that the earlier virus was particularly virulent, but there was still doubt as to whether it was its virulence or the poor sanitary and medical conditions of 1918 that contributed the most to such a high mortality rate.

In a paper published in the January 18 issue of Nature, a group of Canadian and American researchers have compared the effect of both the 1918 strain and a common influenza strain in macaque monkeys, and theorise that the 1918 flu elicited a very different immune response than common influenza, Professor Yoshihiro Kawaoka from the University of Wisconsin, Madison, said.

The monkeys infected with contemporary influenza were able to fight the infection and recover quite easily. Those infected with the 1918 strain, however, became very ill and all required euthanasia by day eight of the infection.

"We then studied the host responses and found something very unique, an essential difference," he said.

Collaborators at the University of Washington used the rhesus macaque genome, which is currently being sequenced, and macaque-specific oligonucleotide arrays to test the host responses from lung and bronchial tissue, UW's Professor Michael Katze said.

"With the low-pathogenic virus there was a very robust early innate response ... after infection," Katze said. "Following that robust response the monkeys quickly cleared the virus and the host response was down-modulated.

"With the 1918 virus infected lungs and bronchi, we found a slightly muted response early after infection, but the response was not abated, not modulated and not down-regulated.

"Instead, at six and eight days post-infection, the innate response stayed up and didn't go down, so there was an aberrant or uncontrolled inflammatory response."

Katze said this difference was interesting because of the epidemiology of mortality in the 1918 epidemic. "The very young and very old were susceptible as is the case in most flu epidemics and pandemics, but in 1918 young adults in their 20s and 30s had a very high mortality rate.

"One possibility is that instead of protecting the individual, the immune response contributed to its lethality."

Lead author Professor Darwyn Kobasa of Canada's Public Health Agency in Winnipeg said studies of how influenza is able to modulate host innate immune responses had relevance not only to the 1918 pandemic but to more recent strains as well.

"It is not only interesting to find out what happened in 1918 but also very relevant today as we prepare for a possible pandemic caused by an avian H5N1 virus," Kobasa said.

"H5N1 appears to cause illness in a similar way to the 1918 virus. This will help us plan and predict how to use our resources to reduce the impact of a new pandemic."

Aberrant innate immune response in lethal infection of macaques with the 1918 influenza virus appears in the January 18, 2007 issue of Nature.