Final Report Summary - DROSO-PARASITE (Drosophila as a model host to study infections by kinetoplastid parasites)
Neglected Tropical Diseases are the most common diseases of the world’s poorest people. Many are caused by parasites called trypanosomatids that are transmitted to humans via insects belonging to the order of Diptera (also known as true flies). These flies (including tsetse, sand flies and black flies) are difficult to study in the lab and so the prospect of rapid progress in the basic biology of fly-parasite interaction is bleak. However, a model dipteran species with an extensive “tool-box” is the fruit fly Drosophila melanogaster with its natural trypanosomatid Herpetomonas muscarum. Here we establish the framework of their interaction with the view that part of this interaction will represent an evolutionary conserved component of the dipteran response to parasite infection and will inform and accelerate more targeted studies into medically important but difficult to study Diptera.
In Drosophila, parasite infection reduced fecundity but not lifespan in NF-κB/Relish-deficient flies. Gene expression analysis implicated the two NF-κB pathways Toll and Imd and STAT signalling. Tissue specific knock-down of key components of these pathways in enterocytes (ECs) and intestinal stem cells (ISCs) influenced initial numbers, infection dynamics and time of clearance. Herpetomonas triggered STAT activation and proliferation of ISCs. Loss of Relish suppressed the latter, resulting in increased parasite numbers and delayed clearance. Conversely, overexpression of Relish increased ISCs and reduced uptake. Finally, loss of Toll signalling decreased EC numbers and enabled parasite persistence. This network of signalling may represent a general mechanism by which medically important but difficult to study dipteran insects respond early to parasite infection. Early stages are important because it is there when parasite infection is established in the insect gut; by elucidating molecular and cellular events we can think of blocking establishment and therefore we can block transmission to humans.
In Drosophila, parasite infection reduced fecundity but not lifespan in NF-κB/Relish-deficient flies. Gene expression analysis implicated the two NF-κB pathways Toll and Imd and STAT signalling. Tissue specific knock-down of key components of these pathways in enterocytes (ECs) and intestinal stem cells (ISCs) influenced initial numbers, infection dynamics and time of clearance. Herpetomonas triggered STAT activation and proliferation of ISCs. Loss of Relish suppressed the latter, resulting in increased parasite numbers and delayed clearance. Conversely, overexpression of Relish increased ISCs and reduced uptake. Finally, loss of Toll signalling decreased EC numbers and enabled parasite persistence. This network of signalling may represent a general mechanism by which medically important but difficult to study dipteran insects respond early to parasite infection. Early stages are important because it is there when parasite infection is established in the insect gut; by elucidating molecular and cellular events we can think of blocking establishment and therefore we can block transmission to humans.