Image: eraxion/iStockphotoWalter and Eliza Hall Institute researchers have discovered how a key viral gene helps viruses evade early detection by the immune system. Their finding is providing new insights into how viruses are able to establish chronic infections, leading scientists to reevaluate their approaches to viral vaccine development.
Researchers from the institute’s Immunology division together with collaborators at the University of Cambridge (UK) have been studying how the immune system responds to viruses that cause persistent or chronic infections and why the immune system is unable to eliminate these infections.
Dr Gabrielle Belz, Dr Adele Mount and colleagues are particularly interested in immune system cells called dendritic cells and their interaction with viruses that cause chronic infections.
“Chronic infections are one of the greatest health challenges for the Western world, but currently we have very few ways of dealing with them,” Dr Belz said. “They require ongoing medical care and support due to an inability to treat infection effectively.
“We are trying to understand how chronic infections sneak past the usually highly effective immune armoury and covertly establish disease. If we can stop these infections establishing then we can eliminate, or substantially reduce, that societal burden.”
Dendritic cells, which are studied by Dr Belz, Dr Mount and colleagues, act as ‘sentinels’ of the immune system; they are critical for the early detection of invading bacteria and viruses and are one of the first cells to trigger the immune response. “Dendritic cells are called ‘antigen presenting cells’; they digest infectious agents into small fragments and shuttle these fragments to the outside of the cell where they are displayed to virus-specific killer T cells, helping to launch a full-blown immune response,” Dr Belz said.
The team has been investigating a virus called gamma herpesvirus-68, which establishes chronic infections in mice and provides a model of the workings of the human gamma herpesvirus Epstein-Barr Virus, commonly known to cause infectious mononucleosis, or ‘kissing disease’. Their results, which have been published in the Journal of Immunology show that a viral gene called K3 rapidly disables the antigen-processing machinery normally used by dendritic cells to alert the immune system to infections.
“This gene quickly helps the virus to hide from the immune system by subverting normal antigen presentation to T cells, which have the critical task of destroying virally-infected cells,” Dr Belz said. “The virus carries out a top-secret operation. It shuts down the normal mechanisms that allow the immune system to recognise an infection and then boards the antigen-presenting cells which ferry the virus through the blood and tissues, allowing it to spread throughout the body and establish system infection.”
Dr Belz said the study could change conventional views on the best way to generate an immune response to combat chronic infections.
“Our research shows that viral evasion of the immune system in chronic infections happens incredibly early,” Dr Belz said. “Dendritic cells are compromised long before they have the chance to interact with T cells for the next phase of the immune response, so the T cells are never really activated properly. If we want to make an effective vaccine, we need to look at these early escape points used by the virus as the first target for trying to generate a more efficient immune response that will contain the virus and prevent it establishing a systemic infection.”
This work was supported by the National Health and Medical Research Council, the Wellcome Trust, the Swiss National Science Foundation, the Sylvia & Charles Viertel Charitable Foundation and the Howard Hughes Medical Institute.
基因使病毒'看不见'
星期四，2011年1月6日
沃尔特和伊丽莎医学研究所研究馆
eraxion_ - _virus.jpg
图片：eraxion / iStockphoto的
沃尔特和伊丽莎霍尔研究所的研究人员发现了一个关键病毒基因可帮助病毒逃避免疫系统的早期检测。他们的发现是提供对病毒如何能够建立新的见解慢性感染，导致科学家们重新评估他们的方法对病毒疫苗的发展。
从研究所的免疫学的研究人员一起司在剑桥大学（英国）一直在研究免疫系统如何响应病毒引起持续性或慢性感染和免疫系统为什么无法消除这些感染的合作者。
加布里埃尔贝尔斯博士，博士和同事山阿黛勒特别感兴趣的免疫系统细胞称为树突状细胞及其与病毒引起慢性感染的互动。
“慢性感染是为西方世界最大的健康挑战之一，但目前我们已经与他们打交道的方式非常少，”贝尔斯博士说。 “他们需要持续的医疗照顾和支持，由于无法有效地治疗感染。
“我们正试图了解慢性感染潜行过去通常是非常有效的免疫措施;并暗中建立疾病。如果我们能阻止这些感染的话，我们可以建立消除或大大减少，那社会的负担。“
树突状细胞，这是博士贝尔斯博士山和他的同事，因为'哨兵'的免疫系统的行为研究，他们是为入侵细菌和病毒早期检测的关键，而且是最早的细胞之一，触发免疫反应。 “树突状细胞被称为'抗原提呈细胞，它们消化成小片段，这些片段穿梭到哪里，他们都显示给病毒特异性杀伤T细胞的细胞外的传染因子，协助开展一个全面的免疫反应， “博士贝尔斯说。
该小组一直在调查一个叫做伽玛疱疹病毒- 68，它建立在小鼠慢性感染，并提供了人类伽玛EB病毒，俗称引起传染性单核细胞增多，或'接吻病'疱疹病毒的运作模式。他们的研究结果，已发表在免疫学杂志显示，一个名为K3的病毒基因迅速禁用抗原加工机械树突状细胞通常用来警告免疫系统受到感染。
“这有助于病毒基因迅速从免疫系统正常隐藏颠覆抗原提呈给T细胞，它们具有破坏维拉利感染细胞的关键任务，”贝尔斯博士说。 “这种病毒进行了一项绝密行动。它关闭，使免疫系统识别感染，然后板的抗原提呈细胞的正常机制，渡轮通过血液和组织中允许它蔓延到全身，并建立系统感染，病毒等。“
贝尔斯博士表示，这项研究可能改变传统的最佳方式的意见，产生免疫反应，打击慢性感染。
“我们的研究表明，在慢性感染病毒逃避免疫系统发生了令人难以置信的很早，”贝尔斯博士说。 “树突状细胞受到损害很久以前他们有机会与T细胞的免疫反应的下一阶段，因此，T细胞从未真正启动正常。如果我们要作出有效的疫苗，我们需要看看这些早期逃脱作为第一目标的病毒试图产生一个更有效的免疫反应，将含有病毒，防止它建立一个全身性感染的点。“
这项工作得到了国家健康与医学研究委员会，威康信托基金会，瑞士国家科学基金会，西尔维亚＆查尔斯Viertel慈善基金会和霍华德休斯医学研究所。