Scientists find way to boost virus-fighter in cells
before infection is present
Newswise, August 15, 2015— COLUMBUS, Ohio –
Researchers have discovered a way to trigger a preventive response to a flu
infection without any help from the usual players – the virus itself or
interferon, a powerful infection fighter.
The finding, in both mouse and human cells, suggests
that manipulating a natural process could someday be an alternative way to not
just reduce the severity of the flu, but prevent infection altogether.
“The flu vaccine needs to change every year because
the virus is constantly mutating. What we’re doing is targeting a more
fundamental process that is not specific to any particular strain of the
virus,” said Jacob Yount, assistant professor of microbial infection and
immunity at The Ohio State University and senior author of the study.
After showing in cells that altering the role of one
protein can stop the virus in its tracks, Yount’s lab has begun using
experimental drugs to test this flu prevention strategy in mice. Any
possibility for human use is still many years away, but the scientists’
long-term goal is to develop a vaccine-independent method to prevent flu
infections.
“If we were to have an outbreak of some pandemic
influenza virus similar to what we experienced in 2009, I could envision using
this technique to help people who are particularly vulnerable to infection,” he
said. “It would work best if used before an infection, because the strategy
prevents cells from becoming infected in the first place.”
The research is published in the journal PLOS
Pathogens.
The method involves raising the level of a protein
that is known to be effective against all strains of influenza ever tested. The
trick for infection prevention, however, is boosting that protein’s level in
cells before the virus shows up. Doing that, the scientists discovered in this
study, involves suppressing the function of another protein.
The protein effective against influenza is called
IFITM3, (pronounced I-fit-M-3, for interferon-induced transmembrane protein 3).
Under natural conditions, IFITM3 is produced in
large quantities only after the flu virus is present, so it can reduce the
severity of infection. But the way it targets the virus – by trapping it and
disabling its ability to make copies of itself – means that increasing the
protein level before the flu ever arrives would prevent infection from
occurring.
Enough IFITM3 is produced in all cells to maintain a
small but steady presence, but it has a short lifespan. If a cell doesn’t see a
need for its virus-fighting function, the protein is degraded. However, when
flu virus does invade a cell, the cell cranks up production of interferon,
which prompts increased production of IFITM3.
Interferon has another role, as well: telling an
enzyme that degrades IFITM3 to hold off on that job so the IFITM3 level can
stay high and fend off an influenza attack. This enzyme, also a protein, proved
to be the silver bullet in Yount’s work on flu prevention.
The enzyme is called NEDD4 (pronounced Ned-4), and
it degrades IFITM3 by attaching a small chain of molecules to it – a common
process of protein clearing called ubiquitination.
In a series of experiments in mouse and human lung
cells, Yount and colleagues showed that inhibiting NEDD4 from doing this job
led to an accumulation of IFITM3 in the cells and greater resistance to
infection by flu viruses.
IFITM3 is known to be important to humans because
previous research has shown that it is the only identified protein containing a
frequent genetic mutation linked to severe flu infections. Mice – and their
cells – are effective models for this research because mice lacking the same
IFITM3 protein are highly susceptible to flu infections.
Being able to stimulate this response is important
for many reasons, not the least of which is keeping interferon out of the process.
Interferon’s infection-fighting power is accompanied by severe side effects –
most commonly associated with its former use as a treatment for Hepatitis C –
that include, not surprisingly, flu-like symptoms.
“We figured out a way to induce just this single
interferon response – the most important thing interferon does for flu,” Yount
said. “That was a huge finding – that you don’t need an infection or interferon
to increase the level of IFITM3. The steady-state level of the protein is
enough to inhibit the virus if you get rid of NEDD4.”
Exactly how – and when – to get rid of NEDD4 remains
an open question. Without this enzyme, embryonic mice cannot survive to birth,
indicating it is important to fetal development. But later in life, lacking
NEDD4 might not pose any health problems – which is why Yount is currently
testing the effects of suppressing NEDD4 on adult mice.
This work was supported by grants from the National
Institute for Allergy and Infectious Diseases. Yount completed the research
with co-authors Nicholas Chesarino and Temet McMichael, both Ohio State
graduate students.
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