Hepcidin and its Regulatory Pathways in Malaria and in Adaptive Immunity

Lead Research Organisation: University of Oxford

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.

Publications

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Pasricha SR (2018) Hemoglobinopathies in the Fetal Position. in The New England journal of medicine

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Ryan JD (2017) Short-Term versus Long-Term Blood Storage. in The New England journal of medicine

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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

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Spottiswoode N (2017) Role of Activins in Hepcidin Regulation during Malaria. in Infection and immunity

 
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
 
Description EMBO Short-Term Fellowship
Amount € 3,447 (EUR)
Funding ID EMBO Short-Term Fellowship 7561 
Organisation European Molecular Biology Organisation 
Sector Learned Society
Country European Union (EU)
Start 07/2018 
End 12/2019
 
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 06/2014 
 
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 09/2018 
 
Description IMPRINT: IMmunising PRegnant women and INfants neTwork
Amount £1,931,437 (GBP)
Funding ID MR/R005990/1 
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 06/2017 
End 06/2018
 
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 NIHR Haematology Theme Oxford Biomedical Research Centre, Oxford, UK
Amount £200,000 (GBP)
Organisation University of Oxford 
Sector Academic/University
Country United Kingdom
Start 06/2014 
End 03/2021
 
Description Pfizer-Sponsored Rare Disease Consortium Award
Amount £900,000 (GBP)
Organisation Pfizer Inc 
Sector Private
Country United States
Start 04/2015 
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 06/2016 
 
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 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 Academic/University 
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
 
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 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