A rare genetic mutation may be the reason why a small number of children who catch the influenza virus fall so ill they end up in the hospital, sometimes needing ventilators to breathe, scientists say.
Rockefeller University scientists scrutinised blood and tissue samples from a young girl who, at the age of two-and-a-half, developed acute respiratory distress syndrome after catching the flu, and ended up fighting for her life in the hospital.
Years after her ordeal, which she survived, scientists led by Jean-Laurent Casanova found that it could be explained by a rare mutation she carries that prevented her from producing a protein, interferon, that helps fight off the virus.
"This is the first example of a common, isolated and life-threatening infection of childhood that is shown to be also a genetic disease," said Casanova.
"This finding suggests that one could treat severe flu of childhood with interferon, which is commercially available," said Casanova.
Michael J Ciancanelli, a research associate and senior member of Casanova's lab, and his colleagues sequenced all genes in the genomes of the young girl and her parents, looking for mutations that might explain her vulnerability.
Knowing how rare her reaction to the flu was, they narrowed their search to mutations that were unique to her, then focused only on those that affected the immune system.
They found that the girl had inherited two differently mutated copies of the gene IRF7, which encodes a protein that amplifies the production of interferon.
"No other mutations could have explained her reaction to the influenza virus. Each mutation is very uncommon and thus the likelihood of carrying two damaged copies of the gene is extremely rare," said Ciancanelli.
When researchers infected a sample of her blood cells that normally produce interferon - plasmacytoid dendritic cells - they measured no interferon.
In contrast, blood cells from her parents, who each carried only one mutated version of the gene, produced healthy amounts of interferon when exposed to influenza.
"That really was definitive proof that a single, non-mutated copy of this gene is enough to allow people to mount a response to the virus," said Ciancanelli.
The researchers also employed a cutting-edge technology developed by their collaborators at Columbia University to reprogramme the child's skin cells into early progenitor cells, then differentiate those into lung cells, the front lines of influenza infections.
Not surprisingly, the virus replicated more in the patient's cells than in the same cells from healthy people.
Although the patient remains susceptible to severe reactions to new influenza viruses, annual vaccination against seasonal flu has, so far, prevented the occurrence of severe symptoms, indicating that IRF7 is not needed for adaptive immunity to secondary infection by a flu virus, researchers said.
