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

被忽视的热带疾病，如昏睡病、利什曼病、钩虫感染、河盲症和象皮病是世界上最贫穷的人最常见的感染，也是低收入和中等收入国家慢性残疾和贫困的主要原因。非传染性疾病尤其影响育龄儿童和年轻妇女，因此剥夺了他们的健康和经济潜力。非关税壁垒还损害农业生产力，是世界上生活在贫困线以下的最贫穷的14亿人无法摆脱贫困和绝望的一个重要原因。例如，非洲锥虫引起的人类昏睡病是撒哈拉以南非洲36个国家的地方病，4亿居民中有7000万人处于危险之中。非洲大陆正在从一种流行病中恢复过来(1998年有300-50万例)，最近的估计表明，目前每年有5万-7万人感染[世界卫生组织(世卫组织)2006年报告]。昏睡病如果不治疗是致命的。家养动物中的相关疾病每年给非洲农业造成约45亿美元的损失，并对非洲大陆的发展产生了深远的影响。然而，这并不是一个大洲的问题：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、苏丹以及南美洲和拉丁美洲是地方病，而美国南部最贫穷的人中存在利什曼原虫病的问题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破坏性影响，有证据表明它们的全球负担与任何其他严重疾病一样沉重，但对控制和消除努力以及研究和开发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，非关税壁垒甚至没有被具体提及，只是被视为“其他疾病”的一部分(联合国2009年报告)。然而，政策制定者正慢慢开始意识到非关税壁垒的重要性。世卫组织有一个新的被忽视热带病司(WHOTDR)，在联合国机构、会员国和私人慈善机构的支持下，该司有一个新的十年战略计划。然而，需要一场综合攻势来解决非关税壁垒问题。必须在实地和药物输送层面以及研发层面采取行动。关于NTDS在无脊椎动物宿主体内的传播过程以及寄生虫在其昆虫媒介内的生命，我们无法了解许多事情，但事实证明，与昆虫媒介本身合作在技术术语上是非常困难的(实验室中的克隆发展、遗传转化、功能遗传学和基因组学)。这项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上。果蝇黑腹果蝇在免疫学研究中被证明是有用的，它的相关性和贡献在2011年诺贝尔生理学和医学奖中得到了认可。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，并着眼于比较寄生虫感染后沙蝇(利什曼原虫媒介)等昆虫媒介与更容易培养和实验的果蝇的肠道特异性反应。我们将通过DNA微阵列实验和组织特异性RNAi，揭示果蝇体内对赫派单胞菌肠道感染做出反应的宿主基因。然后，我们将击倒那些在感染利什曼原虫后保存在沙蝇中的沙蝇。果蝇和沙蝇属于同一目(它们是双翅目昆虫)，比较它们可以揭示它们对各自原生动物寄生虫的免疫反应的进化、保守或对比的功能特征。

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.