Iron and infection
My lab at the Weatherall Institute of Molecular of Medicine studies the role of iron in infectious diseases and the immune response. Iron is critical for the biochemistry of cells, and is needed equally by host and pathogen; indeed the ‘battle for iron’ is a key determinant of the outcome of infection. We study the molecular basis of this battle, focusing on hepcidin, the iron regulatory hormone (1, 2). Hepcidin controls iron homeostasis analogously to how insulin controls glucose, but unlike insulin, hepcidin is also an acute phase response gene and is upregulated by inflammation. This innate immune activity of hepcidin reflects the importance of iron regulation for host-pathogen interactions.
Using cellular models, transgenic mice and human studies we investigate the signaling pathways that control hepcidin expression and iron homeostasis in the context of a variety of infections and other conditions (3-5). A particularly strong interest is in malaria. With Oxford-based and overseas collaborators, we study how hepcidin and iron relate to the development of malarial anaemia, efficacy of antimalarial treatment and the Plasmodium life-cycle, working in vitro, in mice and in humans (6,7). With partners in The Gambia we translate our basic findings into global health policy by exploring how hepcidin, iron nutrition, and malaria combine to influence anaemia and infection in children (8).
We are also investigating how the immune system uses iron. Immunometabolism is an important field that describes how changes in cellular biochemistry and metabolism regulate differentiation and activity of immune cells. Because of the centrality of iron for key metabolic processes we are studying how iron deficiency (the world’s most common micronutrient deficiency) and iron overload (caused by one of the world’s most common genetic disorders) influence immunometabolism and the immune response. We are interested in how iron availability influences both innate immunity, for example dendritic cells, and adaptive immunity, for example immune memory to vaccines.
A project with clear goals and achievable in 3 months will be designed for students on rotation, either on immunometabolism or on iron-malaria interactions. Students taking up the option of a DPhil placement will have the chance to visit the field station in The Gambia as part of our ongoing collaborations but will mostly be in the WIMM on the JR site.
We work in cell culture, in animal models and with human samples and whole humans at individual and population level. Methodologies employed include qPCR, Western blot, ELISA, ChIP, epigenetic analyses, RNAseq, metabolomics, flow cytometry. We are beginning to utilise the CyTOF and Seahorse machines in the WIMM. We also make good use of the BioInformatic facilities in the WIMM.
1) Hepcidin and the iron-infection axis. Drakesmith H, Prentice AM. Science. 2012;338:768-72
2) Ironing out Ferroportin. Drakesmith H, Nemeth E, Ganz T. Cell Metab. 2015 Nov;22:777-87.
3) Hepcidin is regulated by promoter-associated histone acetylation and HDAC3. Pasricha SR, Lim PJ, Duarte TL, Casu C, Oosterhuis D, Mleczko-Sanecka K, Suciu M, Da Silva AR, Al-Hourani K, Arezes J, McHugh K, Gooding S, Frost JN, Wray KE, Santos A, Porto G, Repapi E, Gray N, Draper SJ, Ashley N, Soilleux E, Olinga P, Muckenthaler MU, Hughes JR, Rivella S, Milne TA, Armitage AE, Drakesmith H. Nat Commun 2017 In press
4) Induced disruption of the iron regulatory hormone hepcidin inhibits acute inflammatory hypoferremia. Armitage AE, Lim PJ, Frost JN, Pasricha SR, Soilleux EJ, Evans E, Morovat R, Davies B, Gileadi U, Robbins PA, Lakhal-Littleton S, Drakesmith H. J Innate Immun. 2016;8(5):517-28.
5) Distinct patterns of hepcidin and iron regulation during HIV-1, HBV, and HCV infections. Armitage AE, Stacey AR, Giannoulatou E, Marshall E, Sturges P, Chatha K, Smith NM, Huang X, Xu X, Pasricha SR, Li N, Wu H, Webster C, Prentice AM, Pellegrino P, Williams I, Norris PJ, Drakesmith H¶, Borrow P¶. PNAS. 2014 Aug 19;111(33):12187-92.
6) Combinatorial effects of malaria season, iron deficiency, and inflammation determine plasma hepcidin concentration in African children. Atkinson SH, Armitage AE, Khandwala S, Mwangi TW, Uyoga S, Bejon PA, Williams TN, Prentice AM, Drakesmith H. Blood. 2014;123:3221-9.
7) Host mediated regulation of superinfection in malaria. Portugal S, Carret C, Recker M, Armitage AE, Epiphanio S, Newbold C, Drakesmith H, Mota MM. Nature Medicine 2011 Jun;17(6):732-7.
8) Expression of the iron hormone hepcidin distinguishes different types of anemia in African children. Pasricha SR, Atkinson SH, Armitage AE, Khandwala S, Veenemans J, Cox SE, Eddowes LA, Hayes T, Doherty CP, Demir AY, Tijhaar E, Verhoef H, Prentice AM, Drakesmith H. Sci Transl Med. 2014 May 7;6(235):235re3.