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The Drakesmith group investigated an unusual aspect of iron regulation against infection, and stumbled upon a new antiviral pathway

Zika virus illustration credit rcsb protein data bank.jpg © Credit RCSB Protein Data Bank (CC BY 4.0)

The amount of iron in our bodies is controlled by the hormone hepcidin, which is secreted by the liver and regulates how much dietary iron is absorbed after a meal.

But hepcidin also has a role in immunity. In response to infection by almost all bacteria and viruses, our bodies produce more hepcidin, which decreases iron levels. This decrease in iron protects against some types of serious infection, since fast-growing pathogens rely on iron for their proliferation.

 

One notable exception

However, Hepatitis C virus (HCV) infection has the opposite effect: when HCV establishes an infection in the liver, it decreases hepcidin levels, leading to iron accumulation..

In a new study published in Nature Microbiology, Professor Drakesmith and his colleagues investigate this intriguing exception, by studying the how HCV infection alters the signalling pathways that control synthesis of hepcidin.

The team found that HCV inhibits the activity of the Bone Morphogenetic Pathway (BMP) signalling in the liver.

BMP signalling is important for embryonic development and in a variety of adult processes, but in the liver, BMP signalling is critical for the correct control of hepcidin synthesis. This is the first study to show that HCV interferes with BMP signalling, and that this is what leads to a reduction in the production of the regulator hepcidin and, ultimately, an increase in liver iron accumulation.

 

More than just iron

But why does the HCV have an effect on BMP signalling: is it because of BMP signalling’s role in regulating hepcidin levels? Or, does the BMP pathway fight infection in other ways too?

Working in human cell lines the team explored this further, and unexpectedly found that BMP signalling also controls the production of a variety of genes that are involved in fighting virus infections, including the well-studied Type I interferon system. The team showed that switching on the BMP signalling pathway could boost interferon activity, resulting in a better response to virus infection. Indeed, the team showed that even if interferon activity is switched off, as long as BMP signalling is activated, infected cells could effectively inhibit the replication of HCV.

We started this study many years ago to understand the anomalous decrease of hepcidin in HCV infection. The experiments took us down an unexpected route and we ended up working on innate antiviral immunity – this was hard, we needed a lot of help and it took a long time! But finally we discovered something new, which we hope will be of some interest and will stimulate future work. - Prof Drakesmith

The antiviral effect of BMP signalling was evident in the clinic too: an analysis of gene expression in liver biopsies of 26 patients, and genomic studies across a much larger population, both showed that BMP signalling predicted how patients would response to a regimen of antiviral treatment that included interferon.

 

Effective against Hepatitis B and Zika

What’s more, the team found that the antiviral effects of this pathway are not restricted to just HCV infection: in cell lines, BMPs inhibited the replication of Hepatitis B virus and Zika virus, suggesting that the BMP pathway may have broad antiviral activity.

 

 

 

Hal Drakesmith is an Associate Professor of Immunology in the Radcliffe Department of Medicine. His research group is based at the MRC Human Immunology Unit.