IDENTIFYING HOST-PATHOGEN INTERACTIONS WHICH CAUSE SEVERE MALARIA

识别导致严重疟疾的宿主-病原体相互作用

• 批准号: MR/L006529/1
• 负责人: Aubrey Cunnington
• 金额: $ 157.11万
• 依托单位: Imperial College London
• 依托单位国家: 英国
• 项目类别: Fellowship
• 财政年份: 2014
• 资助国家: 英国
• 起止时间: 2014 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FL006529%2F1
• 关键词: IDENTIFYING; HOST; PATHOGEN; INTERACTIONS; CAUSE

Infectious diseases continuously challenge the body's defenses. Perhaps surprisingly, we know rather little about how many infections actually cause serious illness. Often we can't explain why the same infection causes mild illness in one person but kills another. Finding out why this happens is key to finding better treatments.Malaria is one infection we need to understand better. It is a disease caused by tiny parasites within red blood cells which are spread from person to person by the bite of mosquitoes. Malaria infects more than 200 million people every year around the world and kills almost 1 million of them. Some features linked to severe infections have been identified, but we don't really know how these lead to severe illness and death.This research aims to explain how interactions between the body's defenses and the malaria parasite result in differences in the severity of illness. We aim to use a new technique to do this. We will look at all the genes that are simultaneously active in the malaria parasite and the human cells in the blood, to find patterns associated with severe illness. Malaria is an ideal disease to assess with our new technique because all of the parasites live in the blood. This research will help to identify new approaches to the treatment of severe malaria. This could save many lives in the future. If we are successful, we think the approach could also be applied to many other infectious diseases. This research will be carried out by collaborating scientists at Imperial College London, The London School of Hygiene and Tropical Medicine, University of Queensland (Australia), National Institutes of Health (USA) and MRC Laboratories, The Gambia. It draws together world leaders in malaria research, genetics, computing methods and statistics. The research will use stored samples collected from Gambian children with malaria. Some of these children had a mild illness, and some had life-threatening complications. The activity of all the human and parasite genes will be measured with a technique called "RNA Sequencing". A series of advanced computer techniques will be used to find the patterns of gene activity associated with severity of malaria. Once we have identified the patterns associated with severe malaria we will test them in the laboratory to see if we can target them to prevent severe malaria. We do this by deliberately altering genes, or by adding or blocking molecules that are important in generating the patterns we identify. This allows us to be sure our findings are causal, rather than just chance associations. The raw data and all our findings will be made publically available, so that other scientists can use the data to answer other important questions about malaria.

传染病不断挑战人体的防御能力。也许令人惊讶的是，我们对有多少感染实际上会导致严重疾病知之甚少。我们通常无法解释为什么同样的感染会导致一个人轻微的疾病，但会导致另一个人死亡。找出这种情况发生的原因是找到更好治疗方法的关键。疟疾是我们需要更好地了解的一种感染。这是一种由红细胞内的微小寄生虫引起的疾病，通过蚊子的叮咬在人与人之间传播。疟疾每年在世界各地感染超过2亿人，并导致近100万人死亡。一些与严重感染有关的特征已经被确定，但我们并不真正知道这些特征是如何导致严重疾病和死亡的。这项研究旨在解释人体防御和疟疾寄生虫之间的相互作用如何导致疾病严重程度的差异。我们的目标是使用一种新技术来做到这一点。我们将研究在疟疾寄生虫和血液中的人类细胞中同时活跃的所有基因，以找到与严重疾病相关的模式。疟疾是用我们的新技术评估的理想疾病，因为所有的寄生虫都生活在血液中。这项研究将有助于确定治疗严重疟疾的新方法。这可能在未来挽救许多人的生命。如果我们成功了，我们认为这种方法也可以应用于许多其他传染病。这项研究将由帝国理工学院伦敦、伦敦卫生和热带医学院、昆士兰州大学（澳大利亚）、国立卫生研究院（美国）和冈比亚MRC实验室的合作科学家进行。它汇集了疟疾研究、遗传学、计算方法和统计学方面的世界领导人。这项研究将使用从冈比亚疟疾儿童中收集的储存样本。这些儿童中有些患有轻微疾病，有些患有危及生命的并发症。所有人类和寄生虫基因的活性将用一种称为“RNA测序”的技术来测量。一系列先进的计算机技术将被用来寻找与疟疾严重程度相关的基因活动模式。一旦我们确定了与严重疟疾相关的模式，我们将在实验室中对其进行测试，看看我们是否可以针对它们来预防严重疟疾。我们通过故意改变基因，或者通过添加或阻断对产生我们识别的模式很重要的分子来做到这一点。这使我们能够确保我们的发现是因果关系，而不仅仅是偶然的关联。原始数据和我们所有的发现都将以电子方式提供，以便其他科学家可以使用这些数据来回答有关疟疾的其他重要问题。

项目成果

Additional file 1 of Clinical and laboratory features associated with serum phosphate concentrations in malaria and other febrile illnesses

与疟疾和其他发热性疾病血清磷酸盐浓度相关的临床和实验室特征的附加文件 1

• DOI: 10.6084/m9.figshare.11887470
• 发表时间: 2020
• 作者: Ho-Ming Suen

Localised release of matrix metallopeptidase 8 in fatal cerebral malaria.

• DOI: 10.1002/cti2.1263
• 发表时间: 2021
• 期刊: Clinical & translational immunology
• 影响因子: 5.8
• 作者: Georgiadou A;Naidu P;Walsh S;Kamiza S;Barrera V;Harding SP;Moxon CA;Cunnington AJ
• 通讯作者: Cunnington AJ

Review of UK malaria treatment guidelines 2016 (Public Health England Advisory Committee on Malaria Prevention).

2016 年英国疟疾治疗指南审查（英国公共卫生疟疾预防咨询委员会）。

• DOI: 10.1136/archdischild-2017-314343
• 发表时间: 2019
• 期刊: Archives of disease in childhood. Education and practice edition
• 作者: Evans C

Plasmodium Infection Is Associated with Impaired Hepatic Dimethylarginine Dimethylaminohydrolase Activity and Disruption of Nitric Oxide Synthase Inhibitor/Substrate Homeostasis.

• DOI: 10.1371/journal.ppat.1005119
• 发表时间: 2015-09
• 期刊: PLoS pathogens
• 影响因子: 6.7
• 作者: Chertow JH;Alkaitis MS;Nardone G;Ikeda AK;Cunnington AJ;Okebe J;Ebonyi AO;Njie M;Correa S;Jayasooriya S;Casals-Pascual C;Billker O;Conway DJ;Walther M;Ackerman H
• 通讯作者: Ackerman H

Comparative transcriptomic analysis reveals translationally relevant processes in mouse models of malaria.

• DOI: 10.7554/elife.70763
• 发表时间: 2022-01-10
• 期刊: eLife
• 影响因子: 7.7
• 作者: Georgiadou A;Dunican C;Soro-Barrio P;Lee HJ;Kaforou M;Cunnington AJ
• 通讯作者: Cunnington AJ