得克萨斯大学西南医学院研究人员发现,肝炎病毒C侵入肌体时会激活体内免疫反应,但是其可以通过操纵关键蛋白的相互作用将免疫反应关闭。研究具体过程刊登于本周电子版《PANS》。
相同的分子“开/关”控制抵御多种病毒的免疫反应。西南医学中心研究人员对蛋白RIG-I和LGP2相互作用以开、关对乙肝病毒C的免疫反应的过程进行了描述。
病毒入侵细胞时,RIG-I蛋白激活肌体的免疫反应。当病毒被清除后,LGP2蛋白关闭RIG-I信号。RIG-I和LGP2的相互作用在调节免疫反应中至关重要,但研究小组发现肝炎C病毒会破坏这种相互作用,将免疫反应关闭在早期阶段。
文章高级作者、微生物学副教授Michael Gale博士说,可以模仿病毒对这些蛋白的作用,设计出控制宿主免疫反应“开/关”的药物。“为发展治疗疾病的新措施提供了可能性。”
Gale研究小组观注病毒逃避免疫反应的机制。肝炎病毒C可经过静脉内药物注射、输血和性行为传播,是美国肝硬化和肝癌的第一原因,美国有四百万人感染。2005年,Gale博士及其同事在肝炎病毒C的研究过程中取得了几项重大突破。RIG-I蛋白与重要遗传物质结合后,RIG-I改变形状,向其它蛋白发送信号,激发产生干扰素(干扰素是能够停止病毒复制的分子)。研究人员发现病毒启动对RIG-I的反击,产生蛋白酶破坏信号过程,防止产生干扰素,为病毒“复制”放行。但当时并不清楚调节RIG-I信号途径的机制。
最近研究发现,RIG-I和LGP2都含有一个抑制区,此区域是调节RIG-I与其信号分子伴侣(包括LGP2)结合的关键位点,控制免疫反应的开关。“肝炎病毒C和其它病毒劫持这种信号途径,停止免疫反应。”当肌体对病毒的免疫反应过度活跃时,RIG-I的关闭是必需的,在1918年流行的许多流感中都发现的。
Gale小组与其他小组合作,设计新的疗法和药物。他们模仿病毒对RIG-I的作用激发抗病毒反应,或者模仿病毒对LGP2的作用关闭RIG-I活性。在1918年流行的许多流感中都有发现RIG-I关闭使针对病毒的免疫反应过度激活。Gale博士说:“精确协调感染引发的免疫反应,是抗病毒或者免疫调节药物的发展趋势。”
英文原文:
Molecular ‘On/Off Switch’ Controls Immune Defenses Against Viruses
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.
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. Michael 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.