A Single Gene May Determine Why Some People Get So Sick With The Flu

It's hard to predict who will get the flu in any given year. While some people may simply spend a few days in bed with aches and a stuffy nose, others may become so ill that they end up in the hospital.

Until now, researchers could only point generally at differences between flu patients' immune responses. Jean-Laurent Casanova, a professor at Rockefeller University and investigator at Howard Hughes Medical Institute, has been sifting through cases of children with severe flu. He and his colleagues have pinpointed one gene that keeps the immune system from fighting off the flu, and their results were published today in Science.

For this study, Casanova focused on one girl, who was two and a half years old when she was infected with H1N1, more commonly known as swine flu. The girl, whom the researchers call P, was admitted to a pediatric intensive care unit where she was intubated and kept on a ventilator while she was treated.

The girl had no risk factors that might predispose her to severe influenza. "The child did not have pulmonary disease or any congenital problems," Casanova tells Shots. Nor did she have a family history of lung problems or anything that would suggest she could not stage a full-throttle immune response. "It's just life-threatening influenza coming out of the blue," he explains.

So Casanova and his collaborators sequenced the girl's genome, and searched for genes that might keep P from building a strong immune response to fight off the flu. They pinpointed one gene that prevents P from making interferons, proteins that help stop an invading virus from replicating and further spreading through the body.

Interferons are an important part of the immune response because they're an early defense that the body employs to fight disease. "They're made by all cells in the body," says Casanova. "Some cells have weak interferons, and in that case even a seasonal flu virus can be dangerous."

In addition to pinpointing the gene, Casanova and his colleagues used stems cells to grow P's pulmonary cells in vitro. Sure enough, her cells could not produce interferons.

The study helps explain genetic variation changes the way that people fight off viruses. "The response to influenza is genetically impaired," says Casanova. He's hoping that the study will catch the interest of other pediatricians and lead to more patients offering their genomes for further research.

Casanova is also intrigued by interferon therapy, which is sometimes used to help fight multiple sclerosis, hepatitis C and some forms of cancer. "It's a little like insulin to the diabetic; you give a person with diabetes insulin and they're good," he explains. Patients might be able to receive interferon injections to mount a faster immune response, he speculates, instead of waiting for later attacks from B and T cells.

As for P, she made a full recovery from H1N1. Four years later, she gets the flu vaccine each year and has remained healthy. "If she is exposed to influenza after vaccination she can respond to the virus," says Casanova. This is because other parts of P's immune system still effectively defend her body from infection. The flu vaccine, for example, uses an inactive form of influenza to build a response in the body's T cells and B cells.

"She makes T cells and B cells against the virus, so when the virus comes it is immediately killed by those cells even though the interferons aren't working," Casanova explains.

So while it doesn't make sense to sequence children's genomes looking for variants that affect the immune system, Casanova strongly advises that every child receive the flu vaccine. "If this patient had been vaccinated prior to her first infection she would probably have always remained healthy," he says.