得克薩斯大學(xué)西南醫(yī)學(xué)院研究人員發(fā)現(xiàn),，肝炎病毒C侵入肌體時(shí)會(huì)激活體內(nèi)免疫反應(yīng),，但是其可以通過操縱關(guān)鍵蛋白的相互作用將免疫反應(yīng)關(guān)閉。研究具體過程刊登于本周電子版《PANS》,。
相同的分子“開/關(guān)”控制抵御多種病毒的免疫反應(yīng)。西南醫(yī)學(xué)中心研究人員對(duì)蛋白R(shí)IG-I和LGP2相互作用以開、關(guān)對(duì)乙肝病毒C的免疫反應(yīng)的過程進(jìn)行了描述,。
病毒入侵細(xì)胞時(shí)，RIG-I蛋白激活肌體的免疫反應(yīng),。當(dāng)病毒被清除后,，LGP2蛋白關(guān)閉RIG-I信號(hào)。RIG-I和LGP2的相互作用在調(diào)節(jié)免疫反應(yīng)中至關(guān)重要,，但研究小組發(fā)現(xiàn)肝炎C病毒會(huì)破壞這種相互作用,，將免疫反應(yīng)關(guān)閉在早期階段。
文章高級(jí)作者,、微生物學(xué)副教授Michael Gale博士說,，可以模仿病毒對(duì)這些蛋白的作用，設(shè)計(jì)出控制宿主免疫反應(yīng)“開/關(guān)”的藥物,。“為發(fā)展治療疾病的新措施提供了可能性,。”
Gale研究小組觀注病毒逃避免疫反應(yīng)的機(jī)制。肝炎病毒C可經(jīng)過靜脈內(nèi)藥物注射,、輸血和性行為傳播,，是美國(guó)肝硬化和肝癌的第一原因，美國(guó)有四百萬人感染,。2005年,，Gale博士及其同事在肝炎病毒C的研究過程中取得了幾項(xiàng)重大突破,。RIG-I蛋白與重要遺傳物質(zhì)結(jié)合后，RIG-I改變形狀,，向其它蛋白發(fā)送信號(hào),，激發(fā)產(chǎn)生干擾素（干擾素是能夠停止病毒復(fù)制的分子）。研究人員發(fā)現(xiàn)病毒啟動(dòng)對(duì)RIG-I的反擊,，產(chǎn)生蛋白酶破壞信號(hào)過程,，防止產(chǎn)生干擾素，為病毒“復(fù)制”放行,。但當(dāng)時(shí)并不清楚調(diào)節(jié)RIG-I信號(hào)途徑的機(jī)制,。
最近研究發(fā)現(xiàn)，RIG-I和LGP2都含有一個(gè)抑制區(qū),，此區(qū)域是調(diào)節(jié)RIG-I與其信號(hào)分子伴侶（包括LGP2）結(jié)合的關(guān)鍵位點(diǎn),，控制免疫反應(yīng)的開關(guān)。“肝炎病毒C和其它病毒劫持這種信號(hào)途徑,，停止免疫反應(yīng),。”當(dāng)肌體對(duì)病毒的免疫反應(yīng)過度活躍時(shí)，RIG-I的關(guān)閉是必需的,，在1918年流行的許多流感中都發(fā)現(xiàn)的,。
Gale小組與其他小組合作，設(shè)計(jì)新的療法和藥物,。他們模仿病毒對(duì)RIG-I的作用激發(fā)抗病毒反應(yīng),，或者模仿病毒對(duì)LGP2的作用關(guān)閉RIG-I活性。在1918年流行的許多流感中都有發(fā)現(xiàn)RIG-I關(guān)閉使針對(duì)病毒的免疫反應(yīng)過度激活,。Gale博士說：“精確協(xié)調(diào)感染引發(fā)的免疫反應(yīng),，是抗病毒或者免疫調(diào)節(jié)藥物的發(fā)展趨勢(shì)。”
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.
