Serum iron is usually considered to be completely bound to transferrin in basal conditions. Our previous work using a mouse model of chronic infection revealed that a proportion of serum iron binds to proteins other than transferrin, as infection progresses. We termed this transition the “iron-shift” (IS). Our aim was to characterize the kinetics, protein profile and immune regulation of the IS, thus assessing its importance for iron re-distribution and host protection during infection. We infected C57BL/6 or genetically deficient mice with Mycobacterium avium and collected serum after 1 to 8 weeks. Serum proteins were separated using consecutive chromatographies, based on the proteins’ size (SEC), charge (IEX), and hydrophobicity (HIC). LC-MS was performed on the fractions with the highest iron content to identify putative iron-binding proteins. The IS was observed starting three weeks post-infection (PI) in wild-type, IFNg-, iNOS- and CCL2-deficient mice. Contrarily, the IS in TNFa knock-out mice was delayed and occurred only at four weeks PI, independently of the bacterial load. In all cases, the IS remained until the end of the experiments. Our preliminary results suggest that ferritin and/or haptoglobin might play important roles in this process. TNFa may cause alterations in serum iron binding during infection. The understanding of the crosstalk between iron biology and immune response may allow the development of new host-targeted therapies applicable to infections and other pathologies with iron disturbances.

This work was financed by Portuguese national funds through FCT – Fundação para a Ciência e Tecnologia, within the projects EXPL/BIA-BQM/1170/2021 and 2022.03635.PTDC, and PhD fellowship 2023.00714.BD to OF.