Hepcidin and its Regulatory Pathways in Malaria and in Adaptive Immunity

Iron is crucial for health – we need it for our red blood cells and immune system to function. However, iron is equally vital for the organisms that infect us; iron availability to microbes can determine the outcome of infection. This has been known for decades, but recently a small peptide called hepcidin has been identified as the key regulator of human iron transport. Hepcidin is at least as important for iron as insulin is for glucose. We are studying how hepcidin behaves in various infections including malaria, tuberculosis and HIV-1, how hepcidin and the immune system interact, and testing whether new therapies can be based around measurement and manipulation of hepcidin. Most infections increase hepcidin levels, but hepatitis C virus instead lowers hepcidin. We found HCV deactivates the cellular components that normally stimulate synthesis of hepcidin. We hypothesized that this behaviour might be advantageous for HCV if these hepcidin stimulators influenced replication of the virus. This seems to be the case, as we found that boosting the activity of the hepcidin stimulators prevented growth of HCV, due to unexpected antiviral properties that resemble the well-known functions of interferon. Understanding and exploiting this antiviral mechanism may lead to new types of antiviral therapy.

Hepcidin is the hormone that governs iron homeostasis – it is equivalent in importance top the role of insulin in glucose balance. Iron is the most important nutrient in host / pathogen interactions; iron affects the outcome of infection, and infections can also lead to the anaemia of chronic inflammation. We aim to understand the role of hepcidin in major infectious diseases including malaria, tuberculosis, HIV-1, and candidiasis. We wish to understand how hepcidin is influenced by, and influences different types of adaptive immune responses, cellular immune function and vaccine efficacy. We will also test how manipulating hepcidin expression and activity can be used as a way of modulating infection and inflammation. Iron deficiency and anaemia are major global health problem, but iron supplementation to anaemic individuals with high hepcidin is both useless and dangerous. Hepcidin is the major determinant of iron absorption in African children with varied types of anaemias. This means that hepcidin could be a useful diagnostic guide to improve safety and efficacy of iron supplementation, and we have studies planned to test this concept. Generally chronic infection / inflammation leads to persistently raised hepcidin levels and predisposes to anaemia, but the exception is chronic Hepatitis C virus (HCV), which causes low hepcidin and hepatic iron accumulation. We investigated the molecular basis of this phenomenon and found HCV interferes with the bone morphogenetic protein (BMP) signaling network that underpins homeostatic control of hepcidin transcription. Stimulating the BMP pathway restores hepcidin levels, but surprisingly also suppresses HCV replication and renders cells more sensitive to interferon. We now wish to understand how BMP signaling intersects with viral sensing and IFN function, and whether BMPs can be used to inhibit other viruses. Developing our studies on BMP signaling and its antiviral properties has potential benefit for understanding innate immune defences against viruses, and using this knowledge to predict how some patients will respond to infection and current treatment regimens. We are developing new small molecule BMP agonists with antiviral activity that could improve treatment efficacy. The advantage of this approach is that by boosting a hitherto unappreciated arm of innate immune defence we may generate broadly acting antivirals that synergise with current therapies against a variety of viruses.