Iron dysregulation and inflammatory stress erythropoiesis associates with long-term outcome of COVID-19

Aimee L Hanson; Matthew P Mulè; Hélène Ruffieux; Federica Mescia; Laura Bergamaschi; Victoria S Pelly; Lorinda Turner; Prasanti Kotagiri; Cambridge Institute of Therapeutic Immunology and Infectious Disease–National Institute for Health Research (CITIID–NIHR) COVID BioResource Collaboration; Berthold Göttgens; Christoph Hess; Nicholas Gleadall; John R Bradley; James A Nathan; Paul A Lyons; Hal Drakesmith; Kenneth G C Smith

doi:10.1038/s41590-024-01754-8

Iron dysregulation and inflammatory stress erythropoiesis associates with long-term outcome of COVID-19

Nat Immunol. 2024 Mar;25(3):471-482. doi: 10.1038/s41590-024-01754-8. Epub 2024 Mar 1.

Authors

Aimee L Hanson^{1

2}, Matthew P Mulè^{1

2

3}, Hélène Ruffieux⁴, Federica Mescia^{1

2}, Laura Bergamaschi^{1

2}, Victoria S Pelly^{1

2}, Lorinda Turner^{1

2}, Prasanti Kotagiri^{1

2}; Cambridge Institute of Therapeutic Immunology and Infectious Disease–National Institute for Health Research (CITIID–NIHR) COVID BioResource Collaboration; Berthold Göttgens⁵, Christoph Hess^{1

2

6

7}, Nicholas Gleadall^{8

9}, John R Bradley^{2

10

11}, James A Nathan^{1

2}, Paul A Lyons^{1

2}, Hal Drakesmith¹², Kenneth G C Smith^{13

14

15

16}

Affiliations

¹ Cambridge Institute of Therapeutic Immunology and Infectious Disease, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge, UK.
² Department of Medicine, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK.
³ NIH-Oxford-Cambridge Scholars Program, Department of Medicine, University of Cambridge, Cambridge, UK.
⁴ MRC Biostatistics Unit, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK.
⁵ British Heart Foundation Centre of Research Excellence, University of Cambridge, Cambridge, UK.
⁶ NIHR BioResource, Cambridge University Hospitals NHS Foundation, Cambridge Biomedical Campus, Cambridge, UK.
⁷ Department of Haematology, Wellcome and MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK.
⁸ Department of Biomedicine, University and University Hospital Basel, Basel, Switzerland.
⁹ Botnar Research Centre for Child Health (BRCCH), University of Basel and ETH Zurich, Basel, Switzerland.
¹⁰ NHS Blood and Transplant, Cambridge Biomedical Campus, Cambridge, UK.
¹¹ Department of Haematology, University of Cambridge, Cambridge, UK.
¹² MRC Translational Immune Discovery Unit, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK.
¹³ Cambridge Institute of Therapeutic Immunology and Infectious Disease, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge, UK. smith.k@wehi.edu.au.
¹⁴ Department of Medicine, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK. smith.k@wehi.edu.au.
¹⁵ The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia. smith.k@wehi.edu.au.
¹⁶ University of Melbourne, Melbourne, Victoria, Australia. smith.k@wehi.edu.au.

Abstract

Persistent symptoms following SARS-CoV-2 infection are increasingly reported, although the drivers of post-acute sequelae (PASC) of COVID-19 are unclear. Here we assessed 214 individuals infected with SARS-CoV-2, with varying disease severity, for one year from COVID-19 symptom onset to determine the early correlates of PASC. A multivariate signature detected beyond two weeks of disease, encompassing unresolving inflammation, anemia, low serum iron, altered iron-homeostasis gene expression and emerging stress erythropoiesis; differentiated those who reported PASC months later, irrespective of COVID-19 severity. A whole-blood heme-metabolism signature, enriched in hospitalized patients at month 1-3 post onset, coincided with pronounced iron-deficient reticulocytosis. Lymphopenia and low numbers of dendritic cells persisted in those with PASC, and single-cell analysis reported iron maldistribution, suggesting monocyte iron loading and increased iron demand in proliferating lymphocytes. Thus, defects in iron homeostasis, dysregulated erythropoiesis and immune dysfunction due to COVID-19 possibly contribute to inefficient oxygen transport, inflammatory disequilibrium and persisting symptomatology, and may be therapeutically tractable.

MeSH terms

COVID-19*
Disease Progression
Erythropoiesis
Humans
Iron*
Research Personnel
SARS-CoV-2

Substances

Iron

Abstract

MeSH terms

Substances

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