Natural flu-fighting protein discovered in human cells

5 min read

Finding could advance control of influenzas

Harvard researchers report having discovered a family of naturally occurring
antiviral agents in human cells, a finding that may lead to better ways to prevent and treat influenza and other viral infections.

In both 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

“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 with Elledge 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
in today’s early on-line edition of 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
, New England Regional Center of Excellence for Biodefense,
Cancer Research UK the Wellcome Trust, and the Kay Kendall Leukaemia
. 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.