In findings that may lead to better ways to prevent and treat influenza and other viral infections, researchers report the discovery of a family of naturally occurring antiviral agents in human cells.
In experiments in human and mouse cells, the flu-fighting proteins prevented or slowed most virus particles from infecting cells at the earliest stage in the virus lifecycle. The anti-viral action happens sometime after the virus attaches itself to the cell and before it delivers its pathogenic cargo.
"We've uncovered the first-line defense in how our bodies fight the flu virus," said Stephen Elledge, the Gregor Mendel professor of genetics and of medicine at Harvard Medical School (HMS) and a senior geneticist at Brigham and Women's Hospital (BWH). "The protein is there to stop the flu. Every cell has a constitutive immune response that is ready for the virus. If we get rid of that, the virus has a heyday."
"When we knocked the proteins out, we had more virus infection," said geneticist Abraham Brass, an instructor in medicine at HMS and Massachusetts General Hospital (MGH), who led the study first as a postdoctoral fellow in the Elledge research group and then in his own lab at the Ragon Institute. "When we increased the proteins, we had more protection," Brass said.
The native antiviral defenders are also crucial after the cells are infected, Brass and his co-authors found. In the cells, the proteins accounted for more than half of the protective effect of the interferon immune response. Interferon orchestrates a large component of the infection-fighting machinery.
"Interferons gave the cells even more protection, but not if we took away the antiviral proteins," Brass said. The study is published online Dec. 17 in the journal Cell.
The potent interferon response is what makes people feel so sick when their bodies are fighting the flu or when receiving interferons as therapy. "If we can figure out ways to increase levels of this protein without interferon, we can potentially increase natural resistance to some viruses without all the side effects of the interferons," Elledge said.
In the study, the surprisingly versatile antiviral proteins protected cells against several devastating human viruses-not only the current influenza A strains including H1N1 and strains going back to the 1930s, but also West Nile virus and dengue virus. While IFITM did not protect against HIV or the hepatitis C virus, experiments suggested the protein may defend against others, including yellow fever virus.
The researchers do not know how the antiviral proteins deflect this variety of viruses, which use different mechanisms of entry into the cell. The protein family, called interferon-inducible transmembrane proteins (IFITM), was first discovered 25 years ago as products of one of the thousands of genes turned on by interferon. Since then, not much else has been discovered about the IFITM family. Versions of the IFITM genes are found in the genomes of many creatures, from fish to chickens to mice to people, suggesting the antiviral mechanism has been working successfully for millions of years in protecting organisms from viral infections.
In Elledge's lab, Brass began the study as a genetic screen to learn how the body blocks the flu. The researchers had previously run similar screens with hepatitis C virus and with HIV. In the screen, the researchers used small interfering RNA to systematically knock down one gene at a time by depleting the proteins the genes were trying to make. Then they examined what effect each blocked gene had on a cell's response to influenza A virus.