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

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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.