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Engineered molecule amplifies body's immune response

September 29, 2005

Bethesda, MD - By altering a molecule called Stat1, which is involved in cellular immune signaling, scientists have succeeded in making the molecule more responsive and thus more efficient. This old protein with a new twist may eventually be used to improve the body's defense against infection.

Stat1 is involved in immune responses that are initiated by proteins called interferons. These proteins are produced by the cells of the immune system in response to challenges by foreign agents such as viruses, bacteria, parasites and tumor cells. Recently, interferon has also been shown to play a role in the body's surveillance against the development of cancer. Because of this role, recombinant interferon is often used for the treatment of certain fibrotic diseases as well as cancers.

Interferon binds to receptors on the surface of the cell, which then use Stat molecules to send signals to the nucleus to increase the expression of genes needed to defend the host against infection. A balance in the amount of Stat signaling caused by interferon is very important.

"When interferon levels are too low, the host is highly susceptible to infection," explains Dr. Michael J. Holtzman of the Washington University School of Medicine in St. Louis, Missouri. "This also applies to Stat1. Children who are born with genetic deficiencies of Stat1 are also very susceptible to infection. In the more severe case, the children die in infancy of fatal viral infections. In less severe cases, they later develop infections due to mycobacteria. When interferon levels are too high, for example during treatment with interferon, there are side effects due to the increased nonspecific response caused by excessive amounts of interferon."

Dr. Holtzman and his colleagues at the Washington University School of Medicine decided to try to improve the body's defense against infection without causing side effects that occur with interferon treatment by engineering a hyper-responsive Stat1 molecule. By increasing the efficiency of the Stat1 molecule, the host could have the benefits of increased Stat1 signaling even at the low levels of interferon normally present in the body. Their results appear as the "Paper of the Week" in the October 7 issue of the Journal of Biological Chemistry, an American Society for Biochemistry and Molecular Biology journal.

"Our paper is really quite simple in conceptual terms," says Dr. Holtzman. "It is well known that interferon provides a benefit to people by protecting them against infectious diseases and cancer. Unfortunately, administration of interferon is costly and short-lived and has significant side effects. We simply reasoned that it might be possible to improve the benefits of interferon by enhancing the way it produces its beneficial effects. We therefore improved a molecule, known as Stat1, that is responsible for relaying the benefits of interferon in the body."

Their initial in vitro results were promising, and the engineered Stat1 molecule exhibited an increased responsiveness to interferon. Following up on these discoveries, Dr. Holtzman and his colleagues are currently performing gene transfer experiments, using both recombinant viruses and transgenic mice, to establish the benefits of hyper-responsive Stat1 in vivo for treating viral infection and cancer. They are also screening for drugs that might increase Stat1 responsiveness.

These experiments may eventually lead to many improvements in cancer therapy as well as the treatment of other infections. Basically, any situation in which interferon hyper-responsiveness might be beneficial will profit from Dr. Holtzman's research.

"One could use our strategy of improving Stat1 efficiency during the winter months in patients who are at risk for developing serious viral infections, for example children with asthma, or heart disease, or immune compromise," suggests Dr. Holtzman. "It may also be of benefit in situations where interferon therapy has been used, such as treatments for liver disease and lung fibrosis, as well as certain cancers. Improving Stat1 efficiency would allow for much lower doses of interferon to be used, decreasing cost and side effect profile. In terms of diagnosis, it may be possible to screen patients for the level of Stat1 responsiveness to interferon, and if found to be low, that would make them candidates for a strategy to improve Stat1 responsiveness using our methods."

American Society for Biochemistry and Molecular Bi