Hepcidin and its Regulatory Pathways in Malaria and in Adaptive Immunity
Lead Research Organisation:
University of Oxford
Department Name: UNLISTED
Abstract
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.
Technical Summary
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.
Organisations
- University of Oxford (Lead Research Organisation)
- UNIVERSITY OF OXFORD (Collaboration)
- Heidelberg University (Collaboration)
- Pfizer Inc (Collaboration)
- La Jolla Pharmaceutical Company (Collaboration)
- Kymab (Collaboration)
- National Institute for Health Research (Collaboration)
- Medical Research Council (MRC) (Collaboration)
People |
ORCID iD |
Hal Drakesmith (Principal Investigator) |
Publications
Sousa Gerós A
(2020)
The battle for iron in enteric infections.
in Immunology
Preston AE
(2021)
Adaptive immunity and vaccination - iron in the spotlight.
in Immunotherapy advances
Spottiswoode N
(2017)
Role of Activins in Hepcidin Regulation during Malaria.
in Infection and immunity
Denton NF
(2019)
Bone morphogenetic protein 2 is a depot-specific regulator of human adipogenesis.
in International journal of obesity (2005)
Duarte TL
(2024)
Iron overload induces dysplastic erythropoiesis and features of myelodysplasia in Nrf2-deficient mice.
in Leukemia
Ryan JD
(2018)
Hepatic iron is the major determinant of serum ferritin in NAFLD patients.
in Liver international : official journal of the International Association for the Study of the Liver
Frost JN
(2021)
Hepcidin-Mediated Hypoferremia Disrupts Immune Responses to Vaccination and Infection.
in Med (New York, N.Y.)
Pasricha SR
(2017)
Hepcidin is regulated by promoter-associated histone acetylation and HDAC3.
in Nature communications
Gooding S
(2019)
Transcriptomic profiling of the myeloma bone-lining niche reveals BMP signalling inhibition to improve bone disease.
in Nature communications
Littwitz-Salomon E
(2021)
Metabolic requirements of NK cells during the acute response against retroviral infection.
in Nature communications
Related Projects
Project Reference | Relationship | Related To | Start | End | Award Value |
---|---|---|---|---|---|
MC_UU_00008/1 | 31/03/2017 | 30/03/2023 | £2,738,000 | ||
MC_UU_00008/2 | Transfer | MC_UU_00008/1 | 31/03/2017 | 30/03/2023 | £1,821,000 |
MC_UU_00008/3 | Transfer | MC_UU_00008/2 | 31/03/2017 | 30/03/2023 | £2,257,000 |
MC_UU_00008/4 | Transfer | MC_UU_00008/3 | 31/03/2017 | 30/03/2023 | £1,459,000 |
MC_UU_00008/5 | Transfer | MC_UU_00008/4 | 31/03/2017 | 30/03/2023 | £1,346,000 |
MC_UU_00008/6 | Transfer | MC_UU_00008/5 | 31/03/2017 | 30/03/2023 | £1,660,000 |
MC_UU_00008/7 | Transfer | MC_UU_00008/6 | 31/03/2017 | 30/03/2023 | £401,000 |
MC_UU_00008/8 | Transfer | MC_UU_00008/7 | 31/03/2017 | 31/03/2024 | £2,876,000 |
MC_UU_00008/9 | Transfer | MC_UU_00008/8 | 31/03/2017 | 30/03/2023 | £2,568,000 |
MC_UU_00008/10 | Transfer | MC_UU_00008/9 | 31/03/2017 | 30/03/2023 | £2,060,000 |
MC_UU_00008/11 | Transfer | MC_UU_00008/10 | 31/03/2017 | 30/03/2023 | £1,477,000 |
Title | Poem on how iron is transported |
Description | A poem written by a DPhil student in the lab, which I was able to help get published in the scientific literature |
Type Of Art | Creative Writing |
Year Produced | 2022 |
Impact | Has been read out at conferences and used in presentations |
URL | https://pubmed.ncbi.nlm.nih.gov/35929344/ |
Description | BMJ article on proposals to alter recommendations on iron supplementation in the developing world |
Geographic Reach | Multiple continents/international |
Policy Influence Type | Citation in clinical reviews |
Guideline Title | Recommendations for COVID-19 vaccination in patients with non-malignant hematologic diseases "3) Data on the COVID-19 vaccine in the context of chronic iron deficiency is still scarce. However, it is advisable to correct the iron deficiency before administration of the COVID-19 vaccine" |
Description | European Haematology Association guideline on iron deficiency and COVID-19 vaccination |
Geographic Reach | Europe |
Policy Influence Type | Citation in clinical guidelines |
URL | https://ehaweb.org/covid-19/eha-statement-on-covid-19-vaccines/recommendations-for-covid-19-vaccinat... |
Description | EMBO Short-Term Fellowship |
Amount | € 3,447 (EUR) |
Funding ID | EMBO Short-Term Fellowship 7561 |
Organisation | European Molecular Biology Organisation |
Sector | Charity/Non Profit |
Country | Germany |
Start | 06/2018 |
End | 12/2019 |
Description | Effects of iron on paediatric vaccine response |
Amount | $545,000 (USD) |
Organisation | Thrasher Research Fund |
Sector | Charity/Non Profit |
Country | United States |
Start | 08/2020 |
End | 09/2023 |
Description | Exploring how the FAM132B gene links iron homeostasis, energy metabolism and erythropoiesis |
Amount | £50,000 (GBP) |
Organisation | University of Oxford |
Department | Radcliffe Department of Medicine |
Sector | Academic/University |
Country | United Kingdom |
Start | 05/2014 |
Description | Functional and metabolic optimisation of immunotherapy |
Amount | $259,606 (USD) |
Organisation | Emerson Collective |
Sector | Private |
Country | United States |
Start | 07/2019 |
End | 08/2021 |
Description | Human Iron Research in Oxford (HIRO) Fellowship, unrestricted grant from Vifor Pharma |
Amount | £500,000 (GBP) |
Organisation | University of Oxford |
Sector | Academic/University |
Country | United Kingdom |
Start | 08/2018 |
Description | IMPRINT: IMmunising PRegnant women and INfants neTwork |
Amount | £1,931,437 (GBP) |
Funding ID | MR/R005990/1 |
Organisation | Medical Research Council (MRC) |
Sector | Public |
Country | United Kingdom |
Start | 05/2017 |
End | 06/2018 |
Description | IRONMUM |
Amount | £450,000 (GBP) |
Funding ID | IRONMUM |
Organisation | Procter & Gamble |
Sector | Private |
Country | United States |
Start | 04/2022 |
End | 12/2024 |
Description | La Jolla Pharmaceutical Company research grant |
Amount | $400,000 (USD) |
Organisation | La Jolla Pharmaceutical Company |
Sector | Private |
Country | United States |
Start | 12/2016 |
Description | Lactoferrin for improved iron bioavailability and safety |
Amount | $3,568,003 (USD) |
Funding ID | INV-039533 |
Organisation | Bill and Melinda Gates Foundation |
Sector | Charity/Non Profit |
Country | United States |
Start | 03/2022 |
End | 12/2024 |
Description | MN - iron requirement in LMIC via stable isotope |
Amount | $4,662,928 (USD) |
Funding ID | INV-036845 |
Organisation | Bill and Melinda Gates Foundation |
Sector | Charity/Non Profit |
Country | United States |
Start | 11/2021 |
End | 10/2025 |
Description | NIHR Haematology Theme Oxford Biomedical Research Centre, Oxford, UK |
Amount | £200,000 (GBP) |
Organisation | University of Oxford |
Sector | Academic/University |
Country | United Kingdom |
Start | 05/2014 |
End | 03/2021 |
Description | Pfizer-Sponsored Rare Disease Consortium Award |
Amount | £900,000 (GBP) |
Organisation | Pfizer Inc |
Sector | Private |
Country | United States |
Start | 03/2015 |
End | 03/2018 |
Description | Regulation of Iron Redox Metabolism by Tetrahydrobiopterin |
Amount | £24,437 (GBP) |
Organisation | University of Oxford |
Department | Radcliffe Department of Medicine |
Sector | Academic/University |
Country | United Kingdom |
Start | 05/2016 |
Description | The impact of iron deficiency on malaria vaccine immunogenicity and efficacy |
Amount | £160,000 (GBP) |
Organisation | Wellcome Trust |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 09/2018 |
End | 10/2021 |
Description | single cell metallomics |
Amount | £29,647 (GBP) |
Organisation | University of Oxford |
Sector | Academic/University |
Country | United Kingdom |
Start | 01/2021 |
End | 01/2022 |
Title | serum hepcidin measurement |
Description | we have modified and optimised a commercially available Elisa kit to measure hepcidin, the master regulator of iron metabolism, in human serum / plasma |
Type Of Material | Physiological assessment or outcome measure |
Year Produced | 2012 |
Provided To Others? | Yes |
Impact | Blood. 2012 Feb 23;119(8):1922-8. Epub 2012 Jan 6. Hepcidin is the major predictor of erythrocyte iron incorporation in anemic African children. Prentice AM, Doherty CP, Abrams SA, Cox SE, Atkinson SH, Verhoef H, Armitage AE, Drakesmith H. and other publications Atkinson et al Blood 2014; Pasricha et al Sci Transl Med 2014; Armitage et al PNAS 2014 Gates Foundation Global Health Grant to study use of hepcidin to guide iron supplementation |
Description | Do hepcidin and haem enhance the anti-malarial efficacy of artemsinin? |
Organisation | La Jolla Pharmaceutical Company |
Country | United States |
Sector | Private |
PI Contribution | We are testing whether hepcidin and haem enhance the anti-malarial efficacy of artemsinin |
Collaborator Contribution | funding and reagents |
Impact | none yet |
Start Year | 2016 |
Description | Exchanging Expertise across Divisions to Advance Women's Health: |
Organisation | University of Oxford |
Department | Nuffield Department of Obstetrics & Gynaecology |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | We are measuring biomarkers in samples from women from the OxWatch study (pre, during and post pregancy) and training a DPhil student from Anthropology to do lab research. |
Collaborator Contribution | Samples and other data are provided by Nuffield Department of Obstetrics and Gynaecology, we work with Institute of Social and Cultural Anthropology to measure paramters and integrate data into Life History - type frameworks. |
Impact | None yet |
Start Year | 2019 |
Description | Exchanging Expertise across Divisions to Advance Women's Health: |
Organisation | University of Oxford |
Department | Social Sciences Division |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | We are measuring biomarkers in samples from women from the OxWatch study (pre, during and post pregancy) and training a DPhil student from Anthropology to do lab research. |
Collaborator Contribution | Samples and other data are provided by Nuffield Department of Obstetrics and Gynaecology, we work with Institute of Social and Cultural Anthropology to measure paramters and integrate data into Life History - type frameworks. |
Impact | None yet |
Start Year | 2019 |
Description | HIGH Consortium |
Organisation | Medical Research Council (MRC) |
Country | United Kingdom |
Sector | Public |
PI Contribution | Hepcidin measurement, oversight of research, direction of research |
Collaborator Contribution | direction of research, field studies |
Impact | grant from the Bill and Melinda Gates Foundation |
Start Year | 2013 |
Description | Iron and the anti-tumour immune response |
Organisation | University of Oxford |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Experimental work in my laboratory. |
Collaborator Contribution | Provision of reagents and parallel experiments |
Impact | None yet |
Start Year | 2019 |
Description | Testing role of iron regulatory proteins in T-cell biology |
Organisation | Heidelberg University |
Country | Germany |
Sector | Academic/University |
PI Contribution | Expertise on assaying T-cell functions and proliferation |
Collaborator Contribution | Provision of T-cells engineered to enable inducible deletion of iron regulatory proteins |
Impact | None yet |
Start Year | 2018 |
Description | evaluating hepcidin as a diagnostic tool in the OUH Trust |
Organisation | National Institute for Health Research |
Department | NIHR Biomedical Research Centre |
Country | United Kingdom |
Sector | Public |
PI Contribution | We measure hepcidin and design prospective investigations in different patient cohorts (per-operative anaemia, antenatal, intensive care) to test how hepcidin can aid in diagnosis of iron deficiency versus anaemia of inflammation and guide decisions to provide iron therapy; and whether oral or i/v iron should be given. |
Collaborator Contribution | clinical expertise, access to patient groups, ethical permissions |
Impact | an ACF post for a clinician, continued funding from BRC for a technician in my lab multidisciplinary: haematology, immunology, obs + gynae, peri-operative care, intensive care units |
Start Year | 2014 |
Description | new treatments for anaemia of inflammation |
Organisation | Kymab |
Country | United Kingdom |
Sector | Private |
PI Contribution | testing reagents for efficacy in defined experimental systems |
Collaborator Contribution | generation of reagents |
Impact | none yet besides the funding |
Start Year | 2015 |
Description | new treatments for anaemia of inflammation and for iron overload of thalassaemia |
Organisation | Pfizer Inc |
Country | United States |
Sector | Private |
PI Contribution | Business plan to work with Pfizer to develop and test new treatments for anaemia of inflammation and for iron overload of thalassaemia |
Collaborator Contribution | generation of some of the reagents, some of the screening resources |
Impact | employment for two post-docs for three years mutidisciplinary: immunology, haematology, protein biology |
Start Year | 2015 |
Title | ???????????? |
Description | To provide, because it is determined that ERFE binds to and affects the activity of both BMP2 and BMP6, modulation of this interaction that offers means to provide an impact on improving insulin tolerance and ameliorate various aspects of impaired body fat distribution, such as the development of diabetes and metabolic and non-alcoholic fatty liver disease.SOLUTION: The present invention further relates to methods for treating a disease of iron metabolism and disease of fat or carbohydrate metabolism using a BMP agonist or antagonist.SELECTED DRAWING: Figure 1 |
IP Reference | JP2019210290 |
Protection | Patent application published |
Year Protection Granted | 2019 |
Licensed | Yes |
Impact | development ongoing |
Title | METHODS OF TREATING IRON METABOLIC DISEASE WITH A NEUTRALIZING ANTIBODY BINDING ERHYTHROFERRONE |
Description | The present invention further relates to methods for treating a disease of iron metabolism and disease of fat or carbohydrate metabolism using a BMP agonist or antagonist |
IP Reference | WO2019234680 |
Protection | Patent application published |
Year Protection Granted | 2019 |
Licensed | Yes |
Impact | development is ongoing |
Title | METHODS OF TREATING METABOLIC DISEASE |
Description | The present invention further relates to methods for treating a disease of iron metabolism and disease of fat or carbohydrate metabolism using a BMP agonist or antagonist |
IP Reference | CA3045370 |
Protection | Patent application published |
Year Protection Granted | 2019 |
Licensed | Yes |
Impact | development is ongoing |
Title | IRONMUM |
Description | an ongoing clinical trial testing whether nutritional interventions including iron improve vaccine responses and anaemia in pregnant women receiving maternal immunisations, on the Thai-Myanmar border |
Type | Preventative Intervention - Nutrition and Chemoprevention |
Current Stage Of Development | Early clinical assessment |
Year Development Stage Completed | 2024 |
Development Status | Under active development/distribution |
Impact | further funding for similar iron - vaccine trials has been obtained |
URL | https://classic.clinicaltrials.gov/ct2/show/NCT05385042 |
Description | A public debate about the most import thing that iron does |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Public/other audiences |
Results and Impact | Arranged and spoke at a debate on the most important thing that iron does, as part of the Oxford IF event 2019. The debate was publicised on BBC Oxford radio (I was interviewed), was in a church in Oxford town centre, and was attended by ~80 people. |
Year(s) Of Engagement Activity | 2019 |
URL | https://interestingtalks.in/Oxford/event/fe-fi-fo-fum-battle-for-the-iron-crown/ |
Description | Chair of WIMM Public Engagement Committee |
Form Of Engagement Activity | A formal working group, expert panel or dialogue |
Part Of Official Scheme? | Yes |
Geographic Reach | International |
Primary Audience | Public/other audiences |
Results and Impact | WIMM Newsletter; WIMM Video; WIMM display at MRC 100 event; launch of a WIMM Public Engagement award WIMM Public Engagement database; greater awareness of WIMM members as to the reach and breadth of WIMM activities; aim to increase local, national and international profile of the WIMM |
Year(s) Of Engagement Activity | 2013 |
Description | Creation of a free online illustrative video game illustrating role of vaccine deployment during a global viral pandemic |
Form Of Engagement Activity | Engagement focused website, blog or social media channel |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Schools |
Results and Impact | We generated an interactive video game illustrating the use and challenges of deploying an efficacious vaccine during an ongoing viral pandemic. It was developed in collaboration the Centre for Computational Biology in the MRC WIMM and Goldsmiths University London. It is free to play and was launched initially in August 2020 (I was interviewed about it on BBC South, and there was an article about it in Oxford Mail online. We released the game in a searchable online published format in Jan 2021, from where it has been played 1720 times as of 4th March 2021. |
Year(s) Of Engagement Activity | 2020 |
URL | https://mrcwimm.itch.io/the-vaccination-game |
Description | Exhibition at New Scientist Live, London |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Public/other audiences |
Results and Impact | We have developed a free online computer game that educates on the role of vaccines to combat a global viral pandemic https://mrcwimm.itch.io/the-vaccination-game We took an exhibition to New Scientist Live at the Exel Centre in London in October. https://live.newscientist.com/exhibitors/mrc-human-immunology-unit-mrc-weatherall-institute-molecular-medicine-university-oxford It explained the game, and aspects of immunity and immune responses, and how vaccines worked, with a range of posters and props, and laptops and giant touchscreen |
Year(s) Of Engagement Activity | 2023 |
URL | https://live.newscientist.com/exhibitors/mrc-human-immunology-unit-mrc-weatherall-institute-molecula... |
Description | Governor at Primary school with responsibilty for science teaching |
Form Of Engagement Activity | A formal working group, expert panel or dialogue |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Schools |
Results and Impact | I am a Foundation Governor for a Primary School in Oxford with a special responsibility for the school's science teaching. I communicate with the school's science lead, advise, assist and assess the teaching and science events for the school, and report back to the Full Governing Board. |
Year(s) Of Engagement Activity | 2017,2018,2019 |
Description | Pint of Science webinar on iron and immunity |
Form Of Engagement Activity | Engagement focused website, blog or social media channel |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Other audiences |
Results and Impact | Pint of Science is a popular platform for scientists to present the work to an interested audience consisting of a mix of scientists and science-interested public. |
Year(s) Of Engagement Activity | 2021 |
URL | https://pintofscience.co.uk/event/essential-elements-of-life |
Description | article on iron deficiency in The Times |
Form Of Engagement Activity | A press release, press conference or response to a media enquiry/interview |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Public/other audiences |
Results and Impact | I was the lead contributor to a piece in The Times on how to combat iron deficiency anaemia. |
Year(s) Of Engagement Activity | 2021 |
URL | https://www.thetimes.co.uk/article/how-can-i-combat-iron-deficiency-anaemia-rb0cnzgfv |
Description | multiple news reports of paper on iron and evolution of complex life |
Form Of Engagement Activity | A press release, press conference or response to a media enquiry/interview |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Public/other audiences |
Results and Impact | I was senior author on a paper describing a new model for how iron has influenced the development of complex life, and so is a consideration in the search for exo-planets that may support such life. Reporting was spread across National newspapers (inc Daily Express in UK, but others globally) and multiple popular science news websites (eg Daily Galaxy, Universe Today, SYFY Wire, The Conversation). https://www.ua-magazine.com/2021/12/09/planetary-iron-may-have-driven-evolution-of-complex-life/ https://www.express.co.uk/news/science/1532866/big-bang-breakthrough-secret-ingredient-life-on-earth-iron-nutrient-alien-life https://www.innovationnewsnetwork.com/iron-possibility-life-on-other-planets/18758/ |
Year(s) Of Engagement Activity | 2021,2022 |
URL | https://theconversation.com/how-changing-levels-of-iron-shaped-the-evolution-of-life-on-earth-and-wh... |