柠檬酸铁的抗病毒作用与机制研究

Iron is an essential nutrient for living cells and is crucial for oxygen transport, cellular respiration, and DNA synthesis. However, the interaction between iron and virus infection is largely unknown. Enterovirus 71 (EV71) is a small RNA virus from family Picornaviridae. Most EV71 infection cases occur in infants and children whose immune system has not fully developed. EV71 has caused many epidemics in Asia-pacific region in recent years manifested by hand, foot, and mouth disease (HFMD) and severe complications such as encephalitis and neurogenic pulmonary edema. In China, HFMD is the top one of category C infectious disease. There are millions cases of HFMD and hundreds of deaths each year. Influenza A virus (IAV) is an enveloped negative-stranded RNA virus infecting a wide variety of birds and mammals. IAV infection causes seasonal flu and pandemic flu worldwide and makes heavy socioeconomic burdens. Although there are antiviral drugs on the market, due to the high variation rate of viral genome, high transmission speed of the virus and drug resistance virus emergency, it is still necessary to develop efficient and cheap new generation anti-influenza virus drugs. We have found that an iron salt Ferric Citrate (FeCit) inhibited EV71 replication in multiple cell lines, indicating that iron is involved in not only nutritional metabolism but also anti-viral immunity, and FeCit is also a good anti-viral drug candidate. In this project, we plan to study the in vivo inhibitory effect of FeCit on EV71 infections, which will further demonstrate the application potential of FeCit. We will also test inhibitory effect of FeCit on influenza virus to test its specificity. Finally, we will study the anti-viral mechanism of FeCit and identify FeCit targets that regulate viral replication in host cells, which will not only provide us more biological knowledge of iron element and host-virus interactions but also provide us novel ideas for new drug development.

铁作为生物生存必需的元素，参与氧运输，柠檬酸循环及DNA合成等众多代谢反应。关于铁在病毒感染宿主过程中的作用目前所知甚少。肠道病毒71型引发的手足口病是一种严重危害儿童健康的传染病。中国每年有几百万感染和数百起死亡病例，在丙类传染病中居首位。甲型流感病毒感染引发的季节性流感和全球性大流感每年给国家带来沉重的社会经济负担。目前虽然有针对流感病毒的疫苗和药物，但其高变异性和耐药性毒株的出现仍亟需新型高效廉价的抗病毒药物研发。我们的初步研究发现柠檬酸铁能够抑制EV71在多种细胞内的复制，说明铁具有治疗病毒感染的重要应用潜力。因此本项目计划进一步探索柠檬酸铁能否在动物体内抑制EV71，以及对流感病毒是否也具有抑制作用。本项目还计划研究柠檬酸铁的抗病毒机制，鉴定细胞内参与病毒复制过程的柠檬酸铁靶向蛋白，为铁元素的生物学功能及宿主与病毒相互作用提供新的认识，也为新型药物开发提供新的理论基础。

铁作为生物生存必需的元素，参与氧运输，柠檬酸循环及DNA合成等众多代谢反应;但关于铁在病毒感染宿主过程中的作用目前所知甚少。流感病毒感染引发的季节性流感和全球性大流感每年都带来沉重的社会经济负担。目前虽然有针对流感病毒的疫苗和药物，但其高变异性和耐药性毒株的出现使得新型高效廉价抗病毒药物的研发仍是必要的。艾滋病毒（HIV）感染导致的艾滋病是一种严重破坏免疫系统的慢性感染病，目前还没有治愈方案。寨卡病毒（Zika virus）近期在美洲流行，导致了严重婴儿小头症。肠道病毒71型引发的手足口病是一种严重危害儿童健康的传染病；中国每年有几百万感染和数百起死亡病例，在丙类传染病中居首位。我们的研究发现柠檬酸铁能够抑制上述多种病毒的感染，亚铁离子能够抑制流感病毒和寨卡病毒，说明铁不仅参与营养代谢，而且还参与抗病毒免疫。本研究探索了柠檬酸铁和亚铁离子在体内或体外对上述病毒的抑制作用，并进一步研究了柠檬酸铁和亚铁离子的抗病毒机制。.我们发现铁离子与柠檬酸根离子的组合对于抗病毒效应是必需的，而亚铁离子则可以直接抑制流感病毒和寨卡病毒。 柠檬酸铁能够直接诱导病毒膜融合并抑制病毒从感染细胞的内体中逃逸，而亚铁离子则能直接抑制病毒与宿主细胞的结合。.我们的研究证明了铁元素的广谱抗病毒作用，表明其在抗病毒感染治疗中具有重要应用潜力。