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.
The screen revealed more than 120 genes with potential roles in different stages of infection. Four of those genes, when knocked down, allowed for a robust increase in the infection of cells by influenza A virus. Of these four candidate "restriction factors," the research team concentrated on the IFITM3 protein because of its known link to interferon and found two closely related proteins in the IFITM family with similar activity.
The most distinctive property of the first-line IFITM3 defense is its preventive action before the virus can fuse with the cell, said co-author and virologist Michael Farzan, associate professor of microbiology and molecular genetics at HMS and the New England Primate Research Center. "The virus is unable to make a protein in the cell to counteract the IFITM proteins, because the cell is already primed against the virus," Farzan said. "To find something that hits the flu and hits it so close to the entry stage of the viral life cycle is really interesting and unusual among viral restriction factors."
The researchers have more questions than answers about how the IFITM restriction factors actually work, but they are excited about the range of inquiry the discovery opens up. For example, variations in the protein from person to person may explain differences in people's susceptibility to flu and other viral infections, as well as its severity, the researchers speculate.
And if scientists can understand the mechanism of action, they may be able to design new therapies with even better antiviral actions. The proteins themselves may be useful for defending against infections in animals, like birds and pigs, which might prevent the emergence of new, potentially more dangerous influenza A strains.
In another potential application, if IFITM3 has a role in the chicken embryos or canine cells used to make flu vaccines, inhibiting the proteins may speed up vaccine production, which has been an issue this year with the manufacture of the H1N1 pandemic vaccine.
The research was funded by the Howard Hughes Medical Institute, the Phillip T. and Susan M. Ragon Foundation, the National Institutes of Health, New England Regional Center of Excellence for Biodefense, Cancer Research UK the Wellcome Trust, and the Kay Kendall Leukaemia Foundation. BWH and MGH have filed a U.S. patent application for this technology that relates to the identification and use of host factors to modulate viral replication/growth.
FULL CITATIONCell, published online Dec. 17
Abraham L. Brass,1,2,4,9,* I-Chueh Huang,5,9 Yair Benita,3,10 Sinu P. John,1,10 Manoj N. Krishnan,6 Eric M. Feeley,1 Bethany J. Ryan,1 Jessica L. Weyer,5 Louise van der Weyden,8 Erol Fikrig,6,7 David J. Adams,8 Ramnik J. Xavier,2,3 Michael Farzan,5,* and Stephen J. Elledge4*1-Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard, Charlestown, MA 02129, USA
Brigham and Women's Hospital (BWH) is a 777-bed nonprofit teaching affiliate of Harvard Medical School and a founding member of Partners HealthCare, an integrated health care delivery network. In July of 2008, the hospital opened the Carl J. and Ruth Shapiro Cardiovascular Center, the most advanced center of its kind. BWH is committed to excellence in patient care with expertise in virtually every specialty of medicine and surgery. The BWH medical preeminence dates back to 1832, and today that rich history in clinical care is coupled with its national leadership in quality improvement and patient safety initiatives and its dedication to educating and training the next generation of health care professionals. Through investigation and discovery conducted at its Biomedical Research Institute (BRI), BWH is an international leader in basic, clinical and translational research on human diseases, involving more than 900 physician-investigators and renowned biomedical scientists and faculty supported by more than $485 M in funding. BWH is also home to major landmark epidemiologic population studies, including the Nurses' and Physicians' Health Studies and the Women's Health Initiative.
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