Investigating the behaviour of malaria gametocytes in the skin and their role in transmission to mosquitoes
Primary Supervisor: Matthias Marti
Secondary Supervisor: Leo Carlin
Tertiary supervisor: Matt Gibbins
Malaria remains a global health threat with around 250 million cases and more than 600,000 deaths each year, most of them caused by the apicomplexan parasite Plasmodium falciparum. Despite very promising reductions upon major elimination efforts starting in the early 2000s, the number of cases and deaths have stagnated since 2015. A key aspect of preventing cases and deaths is to interrupt transmission of the parasite from infected humans to mosquitoes, via the uptake of the sexual gametocyte stages of the parasite in a bloodmeal.
A major hurdle in interrupting transmission is that a proportion of malaria-infected individuals are generally asymptomatic, hence do not seek treatment and can be considered a hidden reservoir for malaria. Interestingly, these untreated people are often able to transmit parasites to mosquitoes at very low gametocytaemia. In fact these infection rates can be higher than expected, assuming gametocytes were homogenously distributed throughout the body and knowing that only a small amount of blood (2 microlitres) is taken up by a mosquito during each feed.
In this project we seek to understand this phenomenon, hypothesising that the action of mosquito biting changes the behaviour of gametocytes in the skin.
You will use existing mouse models of malaria, histological techniques and novel intravital microscopy platforms to visually determine the behaviour of gametocytes in the skin and the process of their uptake to the mosquito, something that has not been visualised or investigated in this way before.
Once we understand the mechanics of transmission and the behaviour and interactions of gametocytes with skin tissue, the aim would be for you to generate mutants to try to block this transmission and prevent uptake, first generating P. berghei mutants and then P. falciparum mutants. These will be tested using our intravital setup and an in vitro system developed with collaborators at EMBL Barcelona.
You will receive support from the supervisory team who individually specialise in histology and working with Plasmodium berghei (Dr Matt Gibbins), generating Plasmodium falciparum mutants (Prof Matthias Marti) and intravital microscopy imaging (Dr Leo Carlin).
The project will be based mainly at the School of Infection and Immunity (Gilmorehill Campus) where Matt Gibbins and part of the Marti lab are based, with visits to Leo Carlin’s lab at Cancer Research UK Scotland Institute (Garscube Campus) and the Marti twin lab at University of Zurich, Switzerland.
References:
Lawniczak, M. K., & Eckhoff, P. A. (2016). A computational lens for sexual-stage transmission, reproduction, fitness and kinetics in Plasmodium falciparum. Malaria journal, 15(1), 487. https://doi.org/10.1186/s12936-016-1538-5
Isaïa, J., Rivero, A., Glaizot, O., Christe, P., & Pigeault, R. (2020). Last-come, best served? Mosquito biting order and Plasmodium transmission. Proceedings. Biological sciences, 287(1939), 20202615. https://doi.org/10.1098/rspb.2020.2615
Meibalan, E., Barry, A., Gibbins, M. P., Awandu, S., Meerstein-Kessel, L., Achcar, F., Bopp, S., Moxon, C., Diarra, A., Debe, S., Ouédraogo, N., Barry-Some, I., Badoum, E. S., Fagnima, T., Lanke, K., Gonçalves, B. P., Bradley, J., Wirth, D., Drakeley, C., Guelbeogo, W. M., … Bousema, T. (2021). Plasmodium falciparum Gametocyte Density and Infectivity in Peripheral Blood and Skin Tissue of Naturally Infected Parasite Carriers in Burkina Faso. The Journal of infectious diseases, 223(10), 1822–1830. https://doi.org/10.1093/infdis/jiz680