Abstract
Iron is crucial to the regulation of the host innate immune system and the outcome of many infections. Hepatitis C virus (HCV), one of the major viral human pathogens that depends on iron to complete its life cycle, is highly skilled in evading the immune system. This study presents the construction and validation of a physiologically relevant triple-cell co-culture model that was used to investigate the input of iron in HCV infection and the interplay between HCV, iron, and determinants of host innate immunity. We recorded the expression patterns of key proteins of iron homeostasis involved in iron import, export and storage and examined their relation to the iron regulatory hormone hepcidin in hepatocytes, enterocytes and macrophages in the presence and absence of HCV. We then assessed the transcriptional profiles of pro-inflammatory cytokines Interleukin-6 (IL-6) and interleukin-15 (IL-15) and anti-inflammatory interleukin-10 (IL-10) under normal or iron-depleted conditions and determined how these were affected by infection. Our data suggest the presence of a link between iron homeostasis and innate immunity unfolding among liver, intestine, and macrophages, which could participate in the deregulation of innate immune responses observed in early HCV infection. Coupled with iron-assisted enhanced viral propagation, such a mechanism may be important for the establishment of viral persistence and the ensuing chronic liver disease.
Highlights
Cellular well-being largely depends on iron needed for effective metabolism, energy production and building block biosynthesis [1]
This increase was accompanied by a similar elevation in secreted hepcidin peptide in pooled co-culture supernatants (Figure 1b) that was not observed in supernatants from the mock-infected cells (Figure A1b)
Both mRNA and secreted hepcidin peptide expression remained quite stable when compared to the 24 h controls of the mock-infected co-cultures (Figure A1a,b)
Summary
Cellular well-being largely depends on iron needed for effective metabolism, energy production and building block biosynthesis [1]. Following the absorption of ingested iron in duodenal enterocytes by the apical membrane divalent metal transporter-1 (DMT1), the iron molecules are either complexed by the iron storage protein ferritin in the cytoplasm or exported into circulation by the only known mammalian exporter Ferroportin (FPN). The iron molecules are oxidised by ferroxidase hephaestin and bound anew by iron transporter transferrin (Tf). Plasma membrane transferrin receptor-1 (TfR1) will subsequently import iron into recipient cells through clathrin-mediated endocytosis, and DMT1 located onto the vesicles of the endocytic pathway releases iron molecules into the cytoplasm to be complexed anew by ferritin. Hepcidin orchestrates systemic iron regulation by binding and degrading FPN, thereby inhibiting iron export and sequestering iron intracellularly [1,2,3,4]. Apart from enterocytes, macrophages and hepatocytes play key roles in systemic iron homeostasis, by serving as iron depositories
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