The role of chromatin extracellular traps in host defence of fish against pathogens.

染色质细胞外陷阱在鱼类宿主防御病原体中的作用。

• 批准号: BB/M026132/1
• 负责人: Valerie Smith
• 金额: $ 31.35万
• 依托单位: University of St Andrews
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2015
• 资助国家: 英国
• 起止时间: 2015 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FM026132%2F1
• 关键词: role; chromatin; extracellular; traps; host

Chromatin, a complex of DNA, RNA and protein, is the material that makes up the nucleus of a cell and serves to store genetic information. However, strong evidence has accumulated that it also has a second function, remarkably as a weapon in defence against bacteria and other microbes. In both mammals and invertebrates, some dedicated immune cells involved in inflammation, expel their chromatin in response to the presence of microbes in a controlled and regulated way to the exterior of the cell. It then billows out, like a cloud, to form a mesh that traps pathogens and kills them by virtue of small antibiotic proteins from the cell cytoplasm that become studded on the fibres. Put simply it is a cell death process that enables an immune cell to continue combatting infectious agents even after it has died. The present project aims to investigate this process in fish, as, despite it being widely regarded as an important immune strategy in humans and other mammals, it has not yet been considered in the context of fish health and protection against infection. Disease is a huge problem in fish farming. It causes significant financial losses to the producers and undesirable suffering for the fish. The problem of disease is also likely to worsen as sea temperature rises through climate change. Despite efforts to develop vaccines for fish over recent decades, many do not provide full protection against infections. This is because of strain variability in the pathogens and the structure of the 'memory' component of the fish's immune system that is responsible for producing long-lived antibodies. Instead, fish rely heavily on inflammation, or 'innate' (i.e. inborn) processes, such as phagocytosis (bacteria-eating) and production of natural antibiotic proteins, to protect themselves. Therefore the innate system of fish is an important target for preventing and controlling infection. The proposed research will be directed at Atlantic salmon, as this is the major aquaculture species in the UK, with many fish farms located in Scotland. The work will use in vitro (i.e. cell culture) methods to assess which inflammatory cells in salmon deploy chromatin to kill pathogens, how strong the responses of these cells are and how efficiently pathogens are killed on the chromatin nets. A range of fish pathogens known to cause serious and, for the producers, devastating, diseases in their stock animals will be used in these experiments. These pathogens also include representative types of different microbial groups, so it should be possible to discover if some are able to block, evade or escape chromatin entrapment. To investigate the likely impact of water temperature on this aspect of the fish host defences, the work will compare the strength of the chromatin release response and the efficiency of pathogen killing by cells sampled from fish that have been acclimated to different water temperatures ranging from 9 to 19 degrees Celsius. The highest value in this range covers temperatures experienced by farmed salmon at some sites in Scotland where sea temperatures have already risen, but will be more commonly encountered if coastal water temperatures increase by 2 degrees Celsius, as predicted by some climate change models. This part of the project will help to inform us if farmed fish will become more susceptible to disease under future climatic conditions. The research will generate new information about the importance of a highly novel immune process in fish and thus enable us understand better how pathogens and their host interact. The work may further underpin the development of new compounds, feed additives or strategies to limit the problem of disease in aquaculture.

染色质是DNA、RNA和蛋白质的复合体，是构成细胞核的物质，用于存储遗传信息。然而，越来越多的有力证据表明，它还有第二个功能，特别是作为防御细菌和其他微生物的武器。在哺乳动物和无脊椎动物中，一些参与炎症的专用免疫细胞以受控和调节的方式将其染色质排出细胞外部，以响应微生物的存在。然后，它像云一样滚滚而出，形成一个网状结构，捕捉病原体，并通过细胞质中的小抗生素蛋白质杀死它们，这些蛋白质聚集在纤维上。简单地说，这是一个细胞死亡的过程，使免疫细胞即使在死亡后仍能继续与传染病作斗争。本项目旨在研究鱼类的这一过程，因为尽管它被广泛认为是人类和其他哺乳动物的一种重要免疫策略，但尚未从鱼类健康和防止感染的角度考虑。疾病是养鱼业的一个大问题。它给生产者造成了巨大的经济损失，并给鱼类带来了不受欢迎的痛苦。随着气候变化导致海温上升，疾病问题也可能恶化。尽管近几十年来努力开发鱼类疫苗，但许多疫苗并不能完全预防感染。这是因为病原体的菌株变异性以及鱼类免疫系统中负责产生长寿抗体的“记忆”组件的结构。相反，鱼类严重依赖炎症或“先天”(即先天)过程，如吞噬(吞噬细菌)和产生天然抗生素蛋白来保护自己。因此，鱼类的先天系统是预防和控制感染的重要靶点。这项拟议的研究将针对大西洋鲑鱼，因为这是英国的主要水产养殖物种，许多养鱼场位于苏格兰。这项工作将使用体外(即细胞培养)方法来评估鲑鱼中哪些炎症细胞部署染色质来杀灭病原体，这些细胞的反应有多强，以及病原体在染色质网上的杀灭效率。在这些实验中，将使用一系列已知的鱼类病原体，这些病原体会在他们的家畜中造成严重的、对生产者来说是毁灭性的疾病。这些病原体还包括不同微生物群的典型类型，因此应该有可能发现一些病原体是否能够阻止、逃避或逃避染色质的捕获。为了研究水温对鱼类宿主防御的这一方面的可能影响，这项工作将比较染色质释放反应的强度和从已适应9至19摄氏度不同水温的鱼类中采集的细胞对病原体的杀灭效率。这一范围内的最高值涵盖了苏格兰一些海水温度已经上升的地点养殖三文鱼所经历的温度，但如果沿海水域温度上升2摄氏度，就会更常见，正如一些气候变化模型预测的那样。该项目的这一部分将有助于告诉我们，在未来的气候条件下，养殖的鱼类是否会变得更容易感染疾病。这项研究将产生关于鱼类高度新颖的免疫过程的重要性的新信息，从而使我们能够更好地了解病原体及其宿主是如何相互作用的。这项工作可能会进一步支持新化合物、饲料添加剂或限制水产养殖疾病问题的战略的开发。

项目成果

Genetic and pharmacological inhibition of CDK9 drives neutrophil apoptosis to resolve inflammation in zebrafish in vivo.

• DOI: 10.1038/srep36980
• 发表时间: 2016-11-11
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: Hoodless LJ;Lucas CD;Duffin R;Denvir MA;Haslett C;Tucker CS;Rossi AG
• 通讯作者: Rossi AG

Chromatin extracellular trap release in rainbow trout, Oncorhynchus mykiss (Walbaum, 1792).

• DOI: 10.1016/j.fsi.2020.01.040
• 发表时间: 2020-01
• 期刊: Fish & shellfish immunology
• 影响因子: 4.7
• 作者: A. P. Van;Neila Álvarez de Haro;J. Bron;Andrew P. Desbois

Principles of Immunopharmacology

免疫药理学原理

• 发表时间: 2019
• 作者: Parnham, MJ

Release of chromatin extracellular traps by phagocytes of Atlantic salmon, Salmo salar (Linnaeus, 1758).

• DOI: 10.1016/j.fsi.2021.08.023
• 发表时间: 2021-12
• 期刊: Fish & shellfish immunology
• 影响因子: 4.7
• 作者: Álvarez de Haro N;Van AP;Robb CT;Rossi AG;Desbois AP
• 通讯作者: Desbois AP