1918 flu virus: tiny changes cancel transmissibility

Feb 2, 2007 (CIDRAP News) – Inducing just two small changes in the virus that caused the influenza pandemic of 1918 inhibits the pathogen's ability to spread, researchers reported Thursday, a finding that may help identify potential pandemic flu strains in the future.

Writing in the Feb 2 issue of Science, Terrence Tumpey of the US Centers for Disease Control and Prevention (CDC) and co-authors describe switching out two amino acids in the reconstructed 1918 virus that the team rescued in 2005.

The changes they made at two spots in that virus's hemagglutinin—a surface protein that allows it to bind to cells so it can reproduce—did not affect the virus's ability to replicate or cause disease in laboratory ferrets, but they prevented the disease passing from one ferret to others caged nearby.

"The question we have been asking for years now is: What do influenza viruses with pandemic potential need to create efficient and sustained transmission in the human population," Tumpey said in an interview. "We think these studies will provide a better framework for understanding viruses' pandemic potential."

The dramatic effect of such a simple change in the virus illustrates the difficulty of predicting pandemic strains' emergence, said Michael Osterholm, director of the University of Minnesota Center for Infectious Disease Research and Policy, publisher of the CIDRAP Web site.

The necessary mutations "could be very complicated and could never happen, or they could be just one or two mutations that could happen at any time," he said. "The trillion-dollar question is, Which one of those assumptions is closer to the truth?"

But pressing ahead with the research—which has provoked controversy both for the original viral rescue and for being carried out under moderate biosecurity rather than the highest level—will reduce the uncertainty, according to CDC Director Julie Gerberding.

"With this vital research, we are learning more about what may have contributed to the spread and deadliness of the 1918 pandemic," Gerberding said in a statement. "By better understanding how this virus spreads, we can be better positioned to slow down or stop the spread of the pandemic virus and hence be better prepared for the next pandemic."

The 1918 virus was an avian strain that adapted to humans over a still-unknown period of exposure. The changes made by the research team effectively forced that process a few steps backward, by taking the virus back to a form more adapted to birds.

The process overwrote the virus's preference for where in the respiratory tract it locks on to reproduce, a process that keenly interests flu virologists.

Human-adapted viruses, including the original 1918 virus—an H1N1 strain that was reassembled from victims' tissues—bind to a receptor known as alpha-2,6 SA (for sialic acid). Avian viruses bind to one known as alpha-2,3 SA. Changing a single amino acid in the 1918 virus's hemagglutinin caused it to bind to both receptors in ferrets' lung tissue; changing two amino acids caused it to switch its binding preference completely.

Though all the virus variants caused severe disease in ferrets inoculated with them, only the original virus spread easily to ferrets caged alongside the infected animals. The virus with the single genetic change apparently did infect the neighboring ferrets, but in such low amounts that it did not cause disease. The virus with two changes did not infect neighboring ferrets at all, taking the researchers by surprise.

"I thought there would still be some transmission, because this is a virus that replicates so well," Tumpey said. "I didn't think transmission would be completely abolished."

Though the experiment was designed to explore pandemic strain evolution—and further work could lead to identifying genetic changes that might be early-warning signals of dangerous strains—Tumpey cautioned against applying the results too directly to H5N1 avian flu.

That strain, which has spread across the globe in birds and sickened at least 270 humans, killing 164, has not yet acquired the ability to spread efficiently from person to person.

"It may turn out that the combination of changes needed is unlikely to occur in nature. Maybe H5N1 doesn't have the capacity to make the switch, or if it does it may end up as a virus that doesn't bind or is attenuated," he said. "I personally don't think only two changes will be necessary; I think it will take more than that."

Tumpey TM, Maines TR, Van Hoeven N, et al. A two-amino acid change in the hemagglutinin of the 1918 influenza virus abolishes transmission. Science 2007 Feb 2;315(5812):655-9 [Abstract]

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