Molecular 'on/off switch' controls immune defenses against viruses

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Molecular 'on/off switch' controls immune defenses against viruses

DALLAS — Dec. 25, 2006 — Much like flipping a light switch, the

hepatitis C virus turns on human immune defenses upon entering the

body but also turns off those defenses by manipulating interaction of

key cellular proteins, UT Southwestern Medical Center researchers

have found.

This same molecular " on/off switch " controls immunity against many

viruses, highlighting a potential new target for novel therapeutics

to fight viruses, the researchers report.

In a study available online this week and in an upcoming issue of the

Proceedings of the National Academy of Sciences, UT Southwestern

scientists describe how the proteins RIG-I and LGP2 normally interact

to turn on and off immune response to hepatitis C.

It's known that when a virus invades a cell, the RIG-I protein

triggers the body to generate an immune response. Once the virus has

been cleared out, the LGP2 protein turns off the RIG-I signals.

This interaction between RIG-I and LGP2 is vital for properly

regulating immunity, but viruses such as hepatitis C can disrupt the

normal process to shut down immune defenses early, the research team

found.

" This knowledge will help us design drugs that mimic the viral

effects on these proteins to either activate a host's immune response

or shut it down, " said Dr. Gale, associate professor of

microbiology and the study's senior author. " This holds great

potential in developing new disease therapies, because the tactics

employed by hepatitis C to trigger immune response are similar to

those employed by other viruses such as West Nile, influenza and the

common cold. "

Dr. Gale's research centers on studying the mechanisms viruses use to

evade immune defenses. Of particular interest is the hepatitis C

virus, a blood-borne infection transmitted by intravenous drug use,

blood transfusions and sexual contact. It affects 4 million U.S.

residents and is the nation's leading cause of cirrhosis and liver

cancer.

In 2005 Dr. Gale and his team completed several breakthrough studies

on hepatitis C, discovering that the RIG-I protein binds to viral

genetic material. Then, RIG-I changes its shape and sends signals to

other proteins that spur production of interferon, a molecule that

stops viral replication. The researchers also found that the virus

launches a counterattack on RIG-I, producing a protein called a

protease to disrupt the signaling process, preventing interferon

production and allowing viral replication.

Just how RIG-I signaling is normally regulated, however, hadn't been

known.

In the current study, UT Southwestern researchers found that RIG-I

and LGP2 each contain a repressor domain, a sort of docking site that

controls the actions of each protein. The domain is the key site that

regulates the ability of RIG-I to bind to its signaling partners,

including LGP2, acting as a switch for controlling immune response,

Dr. Gale said.

" Hepatitis C and others viruses hijack this signaling pathway to stop

immune defenses, " he said.

His research team and others are working to design novel therapeutics

and drugs that could mimic viral effects on RIG-I to spur antiviral

response or, conversely, mimic viral effects on LGP2 to shut down RIG-

I activity. RIG-I shutdown would be necessary in cases when the

immune system's response to a virus is dangerously overactive, which

happened in many flu cases during the 1918 pandemic.

" Fine-tuning immune response to infection is where antiviral or

immune regulatory drugs are headed, " said Dr. Gale.

Other UT Southwestern researchers involved in the study were

microbiology postdoctoral researcher and lead author Dr. Takeshi

Saito; microbiology postdoctoral researcher Dr. Yueh-Ming Loo;

graduate student researchers and Owen; and Dr.

Sangita Sinha, an instructor in internal medicine. Researchers from

Kyoto University and Osaka University in Japan also were involved in

the study.

The National Institutes of Health, the Burroughs Wellcome Fund and

Mr. and Mrs. R. Batcheldor supported the study.