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 the Proceedings 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.
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