Abstract

Candida albicans is the most common human fungal pathogen causing mucosal and systemic infections. However, human antifungal immunity remains poorly defined. Here by integrating transcriptional analysis and functional genomics, we identified Candida-specific host defence mechanisms in humans. Candida induced significant expression of genes from the type I interferon pathway in human peripheral blood mononuclear cells. This unexpectedly prominent role of type I interferon pathway in anti-Candida host defence was supported by additional evidence. Polymorphisms in type I interferon genes modulated Candida-induced cytokine production and were correlated with susceptibility to systemic candidiasis. In in vitro experiments, type I interferons skewed Candida-induced inflammation from a Th17 response towards a Th1 response. Patients with chronic mucocutaneous candidiasis displayed defective expression of genes in the type I interferon pathway. These findings indicate that the type I interferon pathway is a main signature of Candida-induced inflammation and has a crucial role in anti-Candida host defence in humans.

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Acknowledgements

R.J.X. was supported by National Institutes of Health grants AI062773, DK043351 and DK83756 and the Helmsley Trust. M.G.N. was supported by an ERC Consolidator grant (ERC-310372). The work in the group of CW is financially supported by the Coeliac Disease Consortium, an Innovative Cluster approved by the Netherlands Genomics Initiative and funded by the Dutch Government (BSIK03009), and by the Netherlands Organization for Scientific Research (NWO VICI grant 918.66.620). We thank Fadi Towfic for helpful discussions, Mathieu Platteel, Astrid Maatman, Soesma Medema-Jankipersadsing, Rutger Modderman, Judith Land and Gosia Trynka for assisting in the stimulation experiments, RNA and DNA analysis, and microarray experiments (immunochip and gene expression). Furthermore, we thank Kornelia Neveling and Petra de Vries for technical assistance with the RNA sequencing experiments.

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Author notes

    • Sanne P. Smeekens
    • , Aylwin Ng
    •  & Vinod Kumar

    These authors contributed equally to this work

Affiliations

  1. Department of Medicine (463), Radboud University Nijmegen Medical Centre, Geert Grooteplein Zuid 8, 6525GA Nijmegen, The Netherlands

    • Sanne P. Smeekens
    • , Theo S. Plantinga
    • , Mark S. Gresnigt
    • , Marije Oosting
    • , Shih-Chin Cheng
    • , Leo A. B. Joosten
    • , Bart-Jan Kullberg
    • , Jos W. M. van der Meer
    •  & Mihai G. Netea
  2. Nijmegen Institute for Infection, Inflammation, and Immunity (N4i) (463), PO Box 9101, 6500 HB Nijmegen, The Netherlands

    • Sanne P. Smeekens
    • , Theo S. Plantinga
    • , Mark S. Gresnigt
    • , Marije Oosting
    • , Shih-Chin Cheng
    • , Leo A. B. Joosten
    • , Bart-Jan Kullberg
    • , Jos W. M. van der Meer
    •  & Mihai G. Netea
  3. The Broad Institute of Massachusetts Institute of Technology and Harvard University, 7 Cambridge Center, Cambridge, Massachusetts 02142, USA

    • Aylwin Ng
    •  & Ramnik J. Xavier
  4. Center for Computational and Integrative Biology and Gastrointestinal Unit, Massachusetts General Hospital, Harvard Medical School, 185 Cambridge Street, Boston, Massachusetts 02114, USA

    • Aylwin Ng
    •  & Ramnik J. Xavier
  5. Department of Genetics, University Medical Centre Groningen, PO Box 30001, 9700 RB Groningen, The Netherlands

    • Vinod Kumar
    • , Cleo van Diemen
    • , Karin Fransen
    • , Suzanne van Sommeren
    •  & Cisca Wijmenga
  6. Duke University Medical Center, Duke Box 102359, Durham, North Carolina 27710, USA

    • Melissa D. Johnson
    •  & John R. Perfect
  7. Department of Clinical Research, Campbell University School of Pharmacy, PO Box 1090, Buies Creek North Carolina 27506, USA

    • Melissa D. Johnson
    •  & John R. Perfect
  8. Department of Human Genetics (855), Radboud University Nijmegen Medical Center, PO Box 9101, 6500 HB Nijmegen, The Netherlands

    • Peer Arts
    • , Eugène T. P. Verwiel
    •  & Alexander Hoischen
  9. Dr John T. Macdonald Foundation Department of Human Genetics and John P. Hussman Institute for Human Genomics, University of Miami, Miller School of Medicine, 1501 NW 10th Avenue, Miami, Florida 33136, USA

    • William K. Scott

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Contributions

L.A.B.J., W.K.S., J.R.P., J.W.M.M., C.W., M.G.N. and R.J.X. designed the research; S.P.S., A.N., V.K., M.D.J., T.S.P., P.A., E.T.V., A.H., C.D., A.G., M.S.G., K.F., S.S., M.O., S.C.C. performed the research and analysed the data; S.P.S., A.N., V.K., C.W., M.G.N. and R.J.X. interpreted the data and wrote the paper.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Mihai G. Netea.

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https://doi.org/10.1038/ncomms2343

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