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Antiviral activity of bone morphogenetic proteins and activins

Abstract

Understanding the control of viral infections is of broad importance. Chronic hepatitis C virus (HCV) infection causes decreased expression of the iron hormone hepcidin, which is regulated by hepatic bone morphogenetic protein (BMP)/SMAD signalling. We found that HCV infection and the BMP/SMAD pathway are mutually antagonistic. HCV blunted induction of hepcidin expression by BMP6, probably via tumour necrosis factor (TNF)-mediated downregulation of the BMP co-receptor haemojuvelin. In HCV-infected patients, disruption of the BMP6/hepcidin axis and genetic variation associated with the BMP/SMAD pathway predicted the outcome of infection, suggesting that BMP/SMAD activity influences antiviral immunity. Correspondingly, BMP6 regulated a gene repertoire reminiscent of type I interferon (IFN) signalling, including upregulating interferon regulatory factors (IRFs) and downregulating an inhibitor of IFN signalling, USP18. Moreover, in BMP-stimulated cells, SMAD1 occupied loci across the genome, similar to those bound by IRF1 in IFN-stimulated cells. Functionally, BMP6 enhanced the transcriptional and antiviral response to IFN, but BMP6 and related activin proteins also potently blocked HCV replication independently of IFN. Furthermore, BMP6 and activin A suppressed growth of HBV in cell culture, and activin A inhibited Zika virus replication alone and in combination with IFN. The data establish an unappreciated important role for BMPs and activins in cellular antiviral immunity, which acts independently of, and modulates, IFN.

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Fig. 1: HCV–BMP pathway interactions decrease hepcidin and associate with therapeutic outcome.
Fig. 2: Enrichment of SMAD1-bound loci proximal to IRF1-bound loci.
Fig. 3: BMP6 increases expression of IRF1 and IRF7 and decreases expression of USP18.
Fig. 4: BMP6 enhances IFN activity.
Fig. 5: BMPs and activins are antiviral against HCV.
Fig. 6: Effects of BMP6 and activin A against HBV and ZIKV.

Data availability

The data that support the findings of this study are available from the corresponding author upon request. The microarray of gene expression profile of HuH7.5 cells treated with 18 nM BMP6 for 24 h is available at the Gene Expression Omnibus under accession no. GSE121073.

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Acknowledgements

The authors thank MRC UK (grant no. 92044), the Wellcome Trust (WT091663MA and 109965MA), NIHR Biomedical Research Centre, Oxford, the Oxford Martin School, the NIH (NIAID U19AI082630, NIDDK R01DK087727, RO1DK-069533 and RO1DK-071837), the Beit Memorial Trust for Medical Research, CORE, The Rosetrees Trust, EU Fund to the University of Zagreb School of Medicine (grant no. KK01.1.1.01.0008) and the GI Research Fund of Dublin, Ireland for funding. The authors also thank A. Townsend and L. Swift for useful discussions and technical guidance.

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L.A.E., K.A.H., N.R., D.N.F., H.T.B., J.A., S.C., J.F., M.B., B.M.J.O. and A.E.A. designed and performed experiments. K.A.H., C.S., E.G. and C.W. performed bioinformatics analyses. J.D.R., S.B., P.F., M.T.G., D.M., J.C. and M.W.L. contributed clinical samples and related patient information. C.C.S., S.V., H.Y.L. and J.L.B. contributed critical reagents and expertise. L.A.E., K.A.H., H.Y.L., J.R., P.J.M., J.L.B., R.T.C., A.E.A., C.W. and P.K. provided intellectual input and contributed to the manuscript. H.D. organized the study and wrote the manuscript.

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Correspondence to Hal Drakesmith.

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Eddowes, L.A., Al-Hourani, K., Ramamurthy, N. et al. Antiviral activity of bone morphogenetic proteins and activins. Nat Microbiol 4, 339–351 (2019). https://doi.org/10.1038/s41564-018-0301-9

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