When a virus such as influenza invades our bodies, interferon
proteins are among the first immune molecules produced to fight off the attack.
Interferon can also play a role in suppressing tumor growth and the effects of
autoimmune diseases, and doctors may use an artificial form of interferon to
treat patients with certain cancers or multiple sclerosis. But even this
approach sometimes fails when patients' bodies reject the foreign interferon or
growing resistant to its effects.
A study by scientists from the University of Pennsylvania School of
Veterinary Medicine offers a new strategy for enhancing the effects of
interferon in fighting off infection. The research suggests that, by targeting
a particular molecule in the interferon signaling pathway, specially designed
drugs may be able to boost the activity of a person's own interferon,
augmenting the immune system's fight against viruses. It's possible that the
same drugs might also be effective against some types of cancer and certain
autoimmune conditions.
Serge Fuchs, a professor of cell biology in Penn Vet's Department
of Animal Biology and director of the School's Mari Lowe Comparative Oncology
Center, was the senior author on the paper published in theProceedings of
the National Academy of Sciences.
"The practical significance of our study is a demonstration
of the ability to use emerging pharmaceuticals to reactivate an individual's
own interferon or to use a reduced dose to get the same effect," Fuchs
said.
Christopher Carbone and Hui Zheng of the Department of Animal
Biology and John Lewis and Alexander Reiter of the Department of Clinical
Studies played leading roles in the study. Additional Penn Vet collaborators
were Sabyasachi Bhattacharya, Paula Henthorn and Kendra Bence. Zhong-Yin Zhang
of Indiana University School of Medicine and Darren Baker of Biogen Idec also
contributed.
The research would have been impossible without the team's
comparative-medicine approach, in which they examined the effects of activating
the interferon pathway in both human cells and in cats affected by a naturally
occurring disease. Mice would normally be the model organism of choice for such
a study, but they lack a molecular element of the interferon pathway that
humans and cats share.
"Mice are very convenient, but they may not always
recapitulate human diseases that well," Fuchs said. "Veterinary
diseases happen naturally, and they provide a less convenient but a more
truthful recapitulation of the human situation."
Interferon fights viruses by binding to an interferon receptor on
cells, triggering a cascade of other molecular events and leading to the
production of proteins that prevent viruses from reproducing or that stimulate
other immune responses. But because too much interferon can harm the host's
body, this signaling cascade has a built-in brake: Using a separate molecular
pathway, interferon triggers the body's cells to remove its own receptor, so
the immune system attack doesn't go on indefinitely.
"It's very important to understand what regulates the
responsiveness of cells to interferon, and a major factor is the levels of
cell-surface receptors," Fuchs said.
Although the researchers' investigations of these pathways led
them to identify a target for improving the body's virus-fighting ability, they
didn't set out to discover a drug. Rather, they were attempting to solve a
paradox of cell biology.
The paradox rests on the fact that many steps in the
interferon-signaling pathway involve adding a molecule of phosphate to proteins
in the cascade. Interferon itself promotes the addition of phosphate onto the
interferon receptor, yet previous evidence suggested that the receptor resisted
being removed by the cell if it had phosphate added. Given that interferon does
in fact trigger the removal of its own receptor, the research team hypothesized
that another enzyme must be at work in the pathway to remove the phosphate
molecule from the receptor so it could be consumed by the body's cells to ramp
down the immune-system response to viruses.
Performing a screening for this putative enzyme, they identified
protein tyrosine phosphatase 1 B (PTP1B) as a likely candidate. In a series of
experiments, the researchers confirmed that blocking PTP1B decreased the
removal of the interferon receptor. As a result, interferon signaling became
enhanced. Using human cells infected with hepatitis C, the researchers found
that adding a PTP1B inhibitor allowed smaller doses of interferon to be
effective in keeping the virus from reproducing. They demonstrated a similar
effect in human cells infected with vesicular stomatitis virus.
Aiding in their work was the fact that pharmaceutical companies
have already designed multiple drugs that inhibit the activity of PTP1B but for
a completely separate reason than the enzyme's involvement in interferon
signaling.
"PTP1B also works on the leptin receptor," Fuchs said.
"This is the pathway that regulates satiety, appetite and weight gain. So
in the past 10 years there have been massive industrial and academic
undertaking to develop PTP1B inhibitors to treat obesity and diabetes."
To see how these PTP1B inhibitors would impact viral infections in
a living organism, the researchers could not use mice because mice lack a
portion of the receptor that PTP1B acts upon, and so blocking PTP1B does not
impact interferon signaling in the same way as it does in humans and other
mammals. Instead, they examined five cats that had been enrolled by their
owners in the study. Each was suffering from chronic stomatitis, a condition
that involves substantial inflammation in the mouth and makes it painful for
the cats to eat and groom. The cats received a single injection of a PTP1B
inhibitor. Two weeks later, all five showed noticeable reductions in redness
and inflammation, providing clinical evidence that these drugs could be used to
treat infection.
Fuchs said that what seemed like a drawback in the study -- that
it couldn't be effectively modeled in mice -- ended up being a benefit, as
naturally occurring diseases in animals such as cat and dogs more closely mimic
many human diseases.
Because interferon is known to suppress tumors and help multiple
sclerosis patients, the results of this study give the researchers optimism
that PTP1B could be a target for anti-cancer and anti-autoimmune disease
therapies.
As a next step, they plan to test the PTP1B inhibitors in a model
of feline immunodeficiency virus, or the cat version of AIDS, to see if its virus-fighting
capabilities can have an effect against that infection.
The study was supported by the National Institutes of Health and
the Mari Lowe Center for Comparative Oncology Research at the University of
Pennsylvania.
Journal Reference:
1. C. J. Carbone, H. Zheng, S. Bhattacharya, J. R.
Lewis, A. M. Reiter, P. Henthorn, Z.-Y. Zhang, D. P. Baker, R. Ukkiramapandian,
K. K. Bence, S. Y. Fuchs. Protein tyrosine phosphatase 1B is a key
regulator of IFNAR1 endocytosis and a target for antiviral therapies.Proceedings
of the National Academy of Sciences, 2012; DOI: 10.1073/pnas.1211491109
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