Mucosal surfaces are exposed to environmental substances and represent a major portal of entry for microorganisms. The innate immune system is responsible for early defense against infections and it is believed that the interferons (IFNs) constitute the first line of defense against viruses. Here we identify an innate antiviral pathway that works at epithelial surfaces before the IFNs. The pathway is activated independently of known innate sensors of viral infections through a mechanism dependent on viral O-linked glycans, which induce CXCR3 chemokines and stimulate antiviral activity in a manner dependent on neutrophils. This study therefore identifies a previously unknown layer of antiviral defense that exerts its action on epithelial surfaces before the classical IFN response is operative.

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We thank K.S. Petersen and I.M. Poulsen for technical assistance and the AU FACS Core facility for technical help. Supported by The Danish Medical Research Council (12-124330 to S.R.P.; 1331-00133B to H.H.W.), the Novo Nordisk Foundation (S.R.P.), the Lundbeck Foundation (R34-3855 to S.R.P.), Aarhus University Research Foundation (S.R.P.), the EU FP7 Mobilex program (1333-00090A to M.K.T.), the US National Institutes of Health (AI065309 to B.C.H.), Faculty of Health Sciences, AU (M.B.I.), the Danish National Research Foundation (DNRF107 to H.H.W.), the Excellence Programme for Interdisciplinary Research (CDO2016 to H.H.W.), the German Research Foundation (DFG, SFB 1054 to J.R.) and the European Research Council (FP7, grant agreement 322865 to J.R.).

Author information

Author notes

    • Line S Reinert
    •  & Martin K Thomsen

    These authors contributed equally to this work.

    • Christian K Holm
    •  & Søren R Paludan

    These authors jointly directed this work.


  1. Department of Biomedicine, University of Aarhus, Aarhus, Denmark.

    • Marie B Iversen
    • , Line S Reinert
    • , Martin K Thomsen
    • , Ramya Nandakumar
    • , Thaneas Prabakaran
    • , Sine K Kratholm
    • , Steen V Petersen
    • , Sebastian Frische
    • , Christian K Holm
    •  & Søren R Paludan
  2. Aarhus Research Center for Innate Immunology, University of Aarhus, Aarhus, Denmark.

    • Marie B Iversen
    • , Line S Reinert
    • , Martin K Thomsen
    • , Ramya Nandakumar
    • , Thaneas Prabakaran
    • , Sine K Kratholm
    • , Christian K Holm
    •  & Søren R Paludan
  3. Department of Cellular and Molecular Medicine, Centre for Glycomics, University of Copenhagen, Copenhagen, Denmark.

    • Ieva Bagdonaite
    • , Sergey Y Vakhrushev
    •  & Hans H Wandall
  4. Department of Pediatrics and Microbiology, Albert Einstein College of Medicine, New York, USA.

    • Natalia Cheshenko
    •  & Betsy C Herold
  5. Department of Regenerative Medicine, Military Institute of Hygiene and Epidemiology, Warsaw, Poland.

    • Malgosha Krzyzowska
  6. Department of Pediatrics, University of Virginia School of Medicine, Charlottesville, Virginia, USA.

    • Fernando Ruiz-Perez
  7. Institute for Medical Immunology, Université Libre de Bruxelles, Gosselies, Belgium.

    • Stanislas Goriely
  8. Department of Biostatistics, University of Aarhus, Aarhus, Denmark.

    • Bo Martin Bibby
  9. Department of Rheumatology and Inflammation Research, University of Gothenburg, Gothenburg, Sweden.

    • Kristina Eriksson
  10. Institut für Klinische Chemie und Pathobiochemie, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.

    • Jürgen Ruland
  11. Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark.

    • Allan R Thomsen


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M.B.I., C.K.H. and S.R.P. conceived of the study; M.B.I., L.S.R., M.K.T., I.B., R.N., N.C., T.P., S.Y.V., M.K. and S.K.K. performed experiments; M.B.I., B.M.B., H.H.W., S.F., C.K.H. and S.R.P. analyzed data; F.R.-P., S.G., K.E., J.R., A.R.T., B.C.H., S.V.P. and H.H.W. provided reagents and intellectual guidance; and M.B.I. and S.R.P. wrote the paper.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Søren R Paludan.

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    Supplementary information on mass spectrometry analysis of HSV-2 O-glycoproteome

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