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A Drosophila-Herpetomonas model as a blueprint to study Leishmania infection in phlebotomine sand flies.

果蝇-疱疹单胞菌模型作为研究白蛉利什曼原虫感染的蓝图。

基本信息

批准号：
BB/K003569/1
负责人：
Petros Ligoxygakis
金额：
$ 54.32万
依托单位：
University of Oxford
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2012
资助国家：
英国
起止时间：
2012 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=BB%2FK003569%2F1
关键词：
Drosophila Herpetomonas model blueprint study

项目摘要

Neglected tropical diseases (NTDs) like sleeping sickness, leishmaniasis, hookworm infections, river blindness and elephantiasis are the most common infections of the world's poorest people and the leading causes of chronic disability and poverty in low- and middle-income countries. NTDs especially affect children and young women of reproductive age and consequently deprive them of their health and economic potential. NTDs also impair agricultural productivity and are an important reason why the world's poorest 1.4 billion people who live below the poverty line cannot escape destitution and despair. For example, human sleeping sickness caused by african trypanosomes is endemic to 36 countries in sub-Saharan Africa with 70 million of the 400 million inhabitants at risk. The continent is recovering from an epidemic (300-500 000 cases in 1998) and recent estimates suggest that there are currently 50-70 000 people infected per year [World Health Organization (WHO) report, 2006]. Sleeping sickness is fatal if left untreated. The related disease (nagana) in domesticated animals causes estimated losses to African agriculture of US$4.5 bn per year and has had a profound effect on development of the continent. However, this is not a problem in one continent: Leishmaniasis, caused by several species of Leishmania is endemic in India, Bangladesh, Nepal, Sudan and South and Latin America, while the existence of an underbelly of Leishmaniasis among the poorest people in the South of the USA came recently into sharp focus. Despite the devastating effect of these diseases on health and development, with evidence that their global burden is as great as that of any other serious disease, financial support for control and elimination efforts, as well as research and development (R&D), have been inadequate. Indeed, in Millennium Development Goal 6 (to "combat HIV/AIDS, malaria and other diseases"), NTDs were not even specifically mentioned but merely considered as part of the "other diseases" (United Nations Report 2009). However, policy makers are slowly beginning to appreciate the importance of NTDs. WHO has a new Department of Neglected Tropical Diseases (WHOTDR), which has a new 10-year strategic plan with support from UN agencies, member states, and private philanthropies. However, an integrated offensive to tackle NTDs is needed. Action must be taken both at the field and drug delivery level as well as at the R&D level. There are a lot of things we are unable to understand about NTDs during the transmission process in the invertebrate host and the life of the parasite inside its insect vector, however working with the insect vectors themselves has proven to be very difficult in technical terms (developing of colonies in the lab, genetic transformation, functional genetics and genomics). This proposal suggests going back to the basic biology of the insect-parasite interaction by using a model "hopping" approach. The fruit fly Drosophila melanogaster has proven informative in immunity studies with its relevance and contribution recognized in the 2011 Nobel prize for Physiology and Medicine. However, the model "hopping" approach that we propose here is a comparative approach, which goes far beyond the level of generic innate immune signalling and looks at comparing gut-specific responses of insect vectors like sand flies (Leishmania vector) following parasite infection with the more easy to culture and do experiments with, fruit fly. We will uncover by DNA microarray experiments and tissue specific RNAi, the host genes responding to Herpetomonas gut infection in fruit flies. We will then knock-down those conserved in sand flies following Leishmania infection. Drosophila and sand flies belong to the same order (they are dipteran insects) and comparing them offers the potential to uncover evolutionary conserved or contrasting functional characteristics in their immune response towards their respective protozoan parasites.

昏睡病、利什曼病、钩虫感染、河盲症和象皮病等被忽视的热带病是世界上最贫穷人口最常见的感染，也是低收入和中等收入国家慢性残疾和贫困的主要原因。被忽视的热带病尤其影响到儿童和育龄青年妇女，从而剥夺了她们的健康和经济潜力。被忽视的热带病还损害农业生产力，是生活在贫困线以下的世界上最贫穷的14亿人无法摆脱贫困和绝望的一个重要原因。例如，由非洲锥虫引起的人类昏睡病在撒哈拉以南非洲36个国家流行，4亿居民中有7000万人面临风险。非洲大陆正在从一场流行病（1998年有300-50万例）中恢复过来，最近的估计表明，目前每年有50-7万人受到感染[世界卫生组织（世卫组织）报告，2006年]。昏睡病如果不及时治疗是致命的。家畜的相关疾病（nagana）估计每年给非洲农业造成45亿美元的损失，并对非洲大陆的发展产生深远影响。然而，这不是一个大陆的问题：由几种利什曼原虫引起的利什曼病在印度、孟加拉国、尼泊尔、苏丹以及南美和拉丁美洲流行，而美国南部最贫困人口中存在的利什曼病最近成为人们关注的焦点。尽管这些疾病对健康和发展造成毁灭性影响，而且有证据表明，它们的全球负担与任何其他严重疾病一样严重，但对控制和消除工作以及研究与发展的财政支持一直不足。事实上，在千年发展目标6（“防治艾滋病毒/艾滋病、疟疾和其他疾病”）中，甚至没有具体提到被忽视的热带病，而只是将其视为“其他疾病”的一部分（《2009年联合国报告》）。然而，决策者正慢慢开始认识到被忽视热带病的重要性。世卫组织设立了一个新的被忽视热带病司，该司在联合国机构、会员国和私人慈善机构的支持下制定了一项新的10年战略计划。然而，需要采取综合攻势来解决被忽视的热带病。必须在现场和给药层面以及研发层面采取行动。在无脊椎动物宿主的传播过程中，关于被忽视热带病，以及寄生虫在其昆虫载体内的生命，我们有很多事情无法理解，然而，从技术角度来看，研究昆虫载体本身是非常困难的（在实验室中培养菌落、遗传转化、功能遗传学和基因组学）。这一建议建议通过使用模型“跳跃”方法回到昆虫-寄生虫相互作用的基本生物学。果蝇黑腹果蝇已被证明在免疫研究中提供信息，其相关性和贡献获得了2011年诺贝尔生理学和医学奖的认可。然而，我们在这里提出的模型“跳跃”方法是一种比较方法，它远远超出了一般先天免疫信号的水平，并将昆虫载体如沙蝇（利什曼原虫载体）在寄生虫感染后的肠道特异性反应与更容易培养和实验的果蝇进行比较。我们将通过DNA芯片实验和组织特异性RNAi来揭示果蝇对疱疹单胞菌肠道感染反应的宿主基因。然后，我们将敲除感染利什曼原虫后在沙蝇中保存的那些基因。果蝇和沙蝇属于同一目（它们是双翅目昆虫），比较它们提供了揭示它们对各自原生动物寄生虫免疫反应的进化保守或对比功能特征的潜力。