Friendly fire blamed in some H1N1 deaths

Study finds poorly targeted immune response in adults born after 1957

Faulty immunological memories could have made middle-aged people more susceptible to the 2009 H1N1 pandemic flu, a new study shows.

Middle-aged people’s bodies tried to defend against H1N1 by hurling antibodies for similar viruses at the new flu. But the old antibodies’ aim wasn’t true and may have ended up backfiring, a study published online December 5 in Nature Medicine suggests.

In most flu seasons, the most vulnerable people are infants and the elderly. But during the 2009 H1N1 influenza pandemic young adults and middle-aged people were hit unusually hard, says Fernando Polack, a viral immunologist at Vanderbilt University in Nashville and a coauthor of the study.

“The middle-aged population usually doesn’t have much of problem,” Polack says. “They miss a few days of work, but they aren’t typically dying in the intensive care unit” as they were during the 2009 pandemic.

Polack and his colleagues set out to determine why the middle-aged, but not the elderly, had such a hard time with the 2009 virus. The researchers collected blood and mucus samples from 65 adults, aged 17 to 57, who had been infected with the 2009 H1N1 swine flu virus. The subjects experienced mild to severe illness: 23 died and 15 of the survivors spent time in an intensive care unit. The team also analyzed samples taken from adults hospitalized with seasonal influenza A viruses and from young Argentinean children infected with the H1N1 virus.

People who died of H1N1 infections had damaged lungs, in which fluid from blood vessels had leaked into tiny air sacs called alveoli, the team found. People with lung damage also had high levels of proteins that are part of the complement system, an evolutionarily ancient component of the immune response. Antibodies direct complement proteins toward bacteria- or virus-infected cells so the proteins can punch deadly holes in the cells’ membranes. Complement proteins also glom on to invaders and attract other immune cells that will then destroy the infection.

Polack and his colleagues found that people born before 1958 had antibodies that could kill the 2009 H1N1 virus. Those people had been exposed to a very similar virus that circulated in the population between 1918 and 1957. The antibodies weren’t a perfect match, but were close enough to neutralize the new virus.

But people born after 1958 didn’t have the protective antibodies. Instead, those people had antibodies against many other flu viruses similar to H1N1, but not a close enough match to actually kill the strain. These mismatched antibodies triggered the complement system, but instead of killing the virus the immune proteins ended up damaging delicate lung tissue, the researchers say.

“This has never been proposed” for influenza viruses, says Adolfo García-Sastre, a microbiologist at Mount Sinai School of Medicine in New York City. “There’s still a lot of debate,” he says, over why middle-aged people fare poorly in some pandemics. Thanks to the new study, “It’s going to be a healthy debate.”

Scientists can now test the new study’s proposed mechanism in animals. “It will open a new avenue of research for influenza,” García -Sastre says.

Polack says he’s happy to have identified a potential mechanism for how pandemic strains kill. Armed with this knowledge, scientists may be able to predict who is at risk in future pandemics and may even consider modulating the immune systems of middle-aged people to prevent self-inflicted lung damage.

Tina Hesman Saey is the senior staff writer and reports on molecular biology. She has a Ph.D. in molecular genetics from Washington University in St. Louis and a master’s degree in science journalism from Boston University.

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