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  • Project No: #OxKEN-2021/19
  • Intake: OxKEN

PROJECT OVERVIEW

Inflammatory responses include upregulation of the iron hormone, hepcidin. Hepcidin drives serum iron down, and this state of hypoferraemia is an ancient highly conserved innate immune defence mechanism that protects against some (bacterial, malaria) infections. However, our recent work shows that hypoferraemia profoundly impairs the development of adaptive immunity, with inhibition of primary CD4, CD8 and B-cell responses and reduced immunological memory. This nutrient trade-off has implications for understanding immunity in the contexts of chronic inflammatory disorders, iron deficiency (the most common micronutrient deficiency worldwide). Furthermore, the concept suggests new methods to control the immune response, via regulation of iron availability to lymphocytes by controlling hepcidin. There are several directions the follow-up research is taking, and a student would be able to choose the specific project that were more interested. In essence, work spans from investigations as to why lymphocytes are so dependent on iron and the consequences of iron deficiency on immune cell function, to much more translational work. Opportunities include: 1) Multi-omic analysis of T-cell metabolism, epigenetic regulation and transcriptomics under conditions of hepcidin-induced hypoferraemia; 2) Tracing of iron trafficking in vivo in immune cells using animal models and humans via single-cell metallomics and imaging of lymph nodes; 3) Testing how iron and iron deficiency influence the immune response to vaccination; 4) Understanding how inflammation and iron control the development of ‘trained immunity’; 5) Manipulating hepcidin to control immune responses in the contexts of viral infection, or immuno-oncology, or transplantation. Each of these opportunities brings with them particular co-supervisors and collaborators and will necessitate the development of certain skill-sets. The student will be able to tailor a project to their own interests to a large degree.

KEYWORDS 

Hepcidin; inflammation; hypoferraemia; T-cells; adaptive immunity

TRAINING OPPORTUNITIES

Animal models, flow and mass cytometry; bioinformatics, ‘omics approaches, combining physiology with immunology, human studies

KEY PUBLICATIONS

  1. Frost et al, Hepcidin-Mediated Hypoferremia Disrupts Immune Responses to Vaccination and Infection. Med, 19th November, 2020. https://doi.org/10.1016/j.medj.2020.10.004
  2. Shah et al, Systemic hypoferremia and severity of hypoxemic respiratory failure in COVID-19. Crit Care, June 2020. https://ccforum.biomedcentral.com/articles/10.1186/s13054-020-03051-w
  3. Prentice et al, Respiratory infections drive hepcidin-mediated blockade of iron absorption leading to iron deficiency anemia in African children. Sci Advances, March 2019. https://advances.sciencemag.org/content/advances/5/3/eaav9020.full.pdf
  4. Pasricha et al, Reducing anaemia in low income countries: control of infection is essential. BMJ, 2018. https://doi.org/10.1136/bmj.k3165
  5. Drakesmith and Prentice, Hepcidin and the iron-infection axis. Science, Nov 2012. https://science.sciencemag.org/content/338/6108/768.abstract

CONTACT INFORMATION OF ALL SUPERVISORS

Alexander Drakesmith