TORONTO — New research supports the theory that the influenza virus that caused the Spanish Flu — the most deadly infectious disease outbreak in known history — wreaked its devastation by turning the immune system of its victims against them.
U.S. scientists reported Wednesday that mice infected with a resurrected version of the killer virus experienced an immediate and overwhelming immune response when compared to the disease process triggered by hybrid viruses fusing genes from the 1918 virus and a more contemporary flu virus.
“You see a lot of tissue degradation and you see hemorrhage — which was something which was observed in 1918 as well in human patients,” said lead author John Kash, a microbiologist from the University of Washington in Seattle.
“That's really not something that you typically associate with influenza infections.”
In a letter published in the journal Nature, Mr. Kash and his co-authors reported on work in which they experimentally infected mice to try to chart not the damage caused by the virus, but how the immune system responded to the assault.
“This is the first study that's looked at the host response,” explained senior author Michael Katze, in whose lab Mr. Kash works.
Most studies of the 1918 virus looked at the infection from the point of view of the virus, trying to determine what about it accounts for its amazing lethality. The Spanish flu pandemic of 1918-1920 is believed to have killed upwards of 50 million people.
“But nobody knows the mechanism of pathogenesis. And the only way to learn about why a virus causes disease is by examining the host response at a global level,” Mr. Katze said.
The analysis tool the team used — called a microarray — allowed them to look at the protein production being switched on or off by upwards of 20,000 mouse genes to try to tease out which specific parts of the immune response were jammed into overdrive by the infection.
Plotting the abnormal immune response could allow scientists to figure out ways to turn down or even switch off the unwanted activity while still allowing the immune system to combat the infection.
“What is the host doing in response to that infection? If you find something different in a virus that's much more virulent, of course you might be able to identify some Achilles heels in that particular (immune) cascade,” explained Dr. Ab Osterhaus, head of virology at Erasmus University in Rotterdam.
The work isn't simply an academic exercise, a forensic effort to try to uncover the techniques of a long-gone killer. If scientists can chart where the immune response went awry with this virus, it might provide clues to the way the immune system responds to other virulent influenza viruses, such as the worrisome H5N1 avian flu. That in turn could point to treatment possibilities.
It could also help public health authorities figure out who in the population might be most at risk from a particular flu virus, said Dr. Michael Osterholm, director of the Center for Infectious Disease Research and Policy at the University of Minnesota.
Unlike many flu strains which target the very young, the sick and the elderly, the 1918 virus took its biggest toll on healthy young adults. Similarly, a disproportionate number of human cases of H5N1 infection have been children and young adults.
“While it may not be readily apparent that there's a public policy implication to what is really an outstanding bench science effort, there is,” Dr. Osterholm said of the study.
“Who should be first to get vaccine and/or drugs has to date been based on the traditional model of seasonal influenza.”
Neither Dr. Osterholm nor Dr. Osterhaus were involved in the study.
Still, the authors acknowledge they haven't proven the exaggerated immune response they saw was responsible for the severity of the disease caused by 1918 infection.
“Our results indicate that enhanced inflammatory and cell death responses might be contributors,” they wrote, but added “it is not possible to completely exclude the possibility that (these) . . . responses may be a consequence rather than the cause.”
Dr. Osterhaus agreed with that assessment, saying the researchers haven't identified where the abnormal immune process could be interrupted. “There's not really a handle on the system, so far.”
