DPHIL SUPERVISOR PROFILE
Professor of Iron Biology
Almost all forms of life require iron to thrive. Iron plays essential biochemical roles in oxygen binding, ATP synthesis and DNA metabolism. During infection, pathogens need to acquire iron from their human host. If iron availability is high, infections can progress more rapidly. On the other hand, denying iron to invading microbes can slow down the course of disease, and allow immune mechanisms more time to clear the infection. Pathogens can become resistant to antibiotics, and can sometimes mutate to avoid recognition by the immune systems, but they cannot escape the metabolic requirement for iron. By manipulating iron transport we hope to develop a new strategy to combat infections.
The human peptide hepcidin is the master controller of iron metabolism; too little hepcidin leads to iron overload, too much causes anaemia. We are defining how hepcidin is modulated during infections, by testing which aspects of pathogen recognition by the host influence hepcidin synthesis. We then will assess whether deliberately altering hepcidin can control experimental infections of iron-requiring bacterial strains.
We are also studying hepcidin regulation in the context of important infectious diseases, namely HIV, malaria and Hepatitis C virus infection. In each of these three diseases imbalances of iron are known to contribute to disease and mortality. For HIV, we found some years ago that the viral protein Nef targets the host protein HFE, which is dysfunctional in the iron-overloading disorder haemochromatosis. By interacting with HFE, HIV manipulates iron transport in infected cells. We are investigating the causes and consequences of altered iron metabolism and hepcidin levels in the context of HIV/AIDS.
In malaria, after a mosquito bite the Plasmodium parasite infects the liver, then invades red blood cells, before differentiating to form gametocytes which leave the human host in a mosquito blood meal, beginning the cycle again. We are investigating the role of hepcidin and iron in each of these life-stages. We have found that the blood stage of infection, associated with anaemia, causes an increase in hepcidin synthesis. If we can block this induction of hepcidin by the parasite we may be able to alleviate malarial anaemia, which is a major cause of illness worldwide.
Finally, hepatitis C virus infection can suppress hepcidin and lead to iron overload. Increased iron is an important co-factor for morbidity in the context of HCV. We are investigating the molecular basis for hepcidin suppression by HCV - if we could reverse it, we may prevent iron overload and in so doing make HCV infection less harmful.
Expression of the iron hormone hepcidin distinguishes different types of anemia in African children.
Pasricha S-R. et al, (2014), Sci Transl Med, 6
Antibodies against the erythroferrone N-terminal domain prevent hepcidin suppression and ameliorate murine thalassemia.
Arezes J. et al, (2020), Blood, 135, 547 - 557
cGAMP loading enhances the immunogenicity of VLP vaccines
Chauveau L. et al, (2020)
Hepcidin-guided screen-and-treat interventions against iron-deficiency anaemia in pregnancy: a randomised controlled trial in The Gambia.
Bah A. et al, (2019), Lancet Glob Health, 7, e1564 - e1574
Minihepcidins improve ineffective erythropoiesis and splenomegaly in a new mouse model of adult beta-thalassemia major.
Casu C. et al, (2019), Haematologica
Twenty Years of Ferroportin Disease: A Review or An Update of Published Clinical, Biochemical, Molecular, and Functional Features.
Vlasveld LT. et al, (2019), Pharmaceuticals (Basel), 12