Controlling malaria through manipulating iron transport
It is estimated two fifths of the world’s population is at risk for malaria, caused by infection with the Plasmodium parasite. Plasmodium has a complex life-cycle, and in mammalian hosts lives in cells in the liver before invading red blood cells. The red blood cell stage is associated with severe illness including anaemia. In the face of increasing drug resistance (Imwong et al, Lancet Infectious Diseases 2017) and in the absence of an effective deployable vaccine, novel strategies for controlling malaria are required, and this entails a better understanding of disease pathogenesis. It is becoming apparent that Plasmodium senses nutrients and alters its behaviour depending on nutrient availability.
Plasmodium needs iron to survive, and obtains its iron from its host. Dietary iron supplements increase the risk of developing malaria (Sazawal et al, The Lancet 2006), and Plasmodium appears to regulate host iron metabolism to protect its growth niche (Portugal et al, Nat Med 2011). Investigating how iron availability influences the growth and life-cycle of the parasite, and harnessing this knowledge to find new ways to combat malaria and malarial anaemia are the key aims of this project. Iron homeostasis in humans is controlled by the small peptide hormone hepcidin (Drakesmith and Prentice, Science 2012) and fluctuations of hepcidin levels occur during malaria (Spottiswoode et al, Infection and Immunity 2017). Hepcidin regulates levels and trafficking of iron; however, the mechanistic interplay between the hepcidin-iron axis and malaria pathogenesis remains poorly characterized. We will investigate how hepcidin influences parasitaemia, anaemia, transmission and resistance to anti-malarials in murine malaria models, including newly generated conditional-hepcidin knockout mice (Armitage et al, J Innate Immun 2016), and by using long-acting hepcidin agonists. We will also investigate whether hepcidin controls the increased susceptibility to Salmonella co-infection that occurs in malaria. Overall, the project will provide a fundamental understanding of how malaria, hepcidin and iron interact.
The student will become familiar will murine models of iron metabolism and of Plasmodium and Salmonella infection. Flow cytometry, mass cytometry (CyTOF), qRT-PCR and RNA-seq, advanced microscopy and protein analytical techniques will be learned and used extensively. We collaborate with other groups overseas and there will be opportunity to travel to these labs and work there. Students will also attend international conferences and present data.
As well as the specific training detailed above, students will have access to a wide-range of seminars and training opportunities through the many research institutes and centres based in Oxford. Students are also able to attend the Methods and Techniques course run by the MRC Weatherall Institute of Molecular Medicine. This course runs through the year, ensuring that students have the opportunity to build a broad-based understanding of differing research techniques.
Generic skills training is offered through the Medical Sciences Division's Skills Training Programme. This programme offers a comprehensive range of courses covering many important areas of researcher development: knowledge and intellectual abilities, personal effectiveness, research governance and organisation, and engagement, influence and impact. Students are actively encouraged to take advantage of the training opportunities available to them.
The Department has a successful mentoring scheme, open to graduate students, which provides an additional possible channel for personal and professional development outside the regular supervisory framework. We hold an Athena SWAN Silver Award in recognition of our efforts to support the careers of female students and staff.
|1||Imwong M, Hien TT, Thuy-Nhien NT, Dondorp AM, White NJ Spread of a single multidrug resistant malaria parasite lineage (PfPailin) to Vietnam. http://www.thelancet.com/journals/laninf/article/PIIS1473-3099(17)30524-8/fulltext|
|2||Sazawal S, Black RE, Ramsan M, Chwaya HM, Stoltzfus RJ, Dutta A, Dhingra U, Kabole I, Deb S, Othman MK, Kabole FM. 2006. Effects of routine prophylactic supplementation with iron and folic acid on admission to hospital and mortality in preschool children in a high malaria transmission setting: community-based, randomised, placebo-controlled trial.Lancet, 367 (9505), pp. 133-43. - http://www.ncbi.nlm.nih.gov/pubmed/16413877|
|3||Portugal S, Carret C, Recker M, Armitage AE, Gonçalves LA, Epiphanio S, Sullivan D, Roy C, Newbold CI, Drakesmith H, Mota MM. 2011. Host-mediated regulation of superinfection in malaria. Nat. Med., 17 (6), pp. 732-7. - http://www.ncbi.nlm.nih.gov/pubmed/21572427|
|4||Drakesmith H, Prentice AM. 2012. Hepcidin and the iron-infection axis.Science, 338 (6108), pp. 768-72. - http://www.ncbi.nlm.nih.gov/pubmed/23139325|
|5||Spottiswoode N, Armitage AE, Williams AR, Fyfe AJ, Biswas S, Hodgson SH, Llewellyn D, Choudhary P, Draper SJ, Duffy P, Drakesmith H. The role of activins in hepcidin regulation during malaria. Infect Immun. 2017 Sep 11. - https://www.ncbi.nlm.nih.gov/pubmed/2889391|
|6||Armitage AE, Lim PJ, Frost JN, Pasricha SR, Soilleux EJ, Evans E, Morovat A, Santos A, Diaz R, Biggs D, Davies B, Gileadi U, Robbins PA, Lakhal-Littleton S, Drakesmith H. Induced Disruption of the Iron-Regulatory Hormone Hepcidin Inhibits Acute Inflammatory Hypoferraemia. J Innate Immun. 2016;8(5):517-28 - https://www.ncbi.nlm.nih.gov/pubmed/27423740|