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Protection against influenza infection requires early recognition by inflammatory dendritic cells through C-type lectin receptor SIGN-R1

Nature Microbiology volume 4, pages 1930–1940 (2019)Cite this article

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Abstract

The early phase of influenza infection occurs in the upper respiratory tract and the trachea, but little is known about the initial events of virus recognition and control of viral dissemination by the immune system. Here, we report that inflammatory dendritic cells (IDCs) are recruited to the trachea shortly after influenza infection through type I interferon-mediated production of the chemokine CCL2. We further show that recruited IDCs express the C-type lectin receptor SIGN-R1, which mediates direct recognition of the virus by interacting with N-linked glycans present in glycoproteins of the virion envelope. Activation of IDCs via SIGN-R1 triggers the production of the chemokines CCL5, CXCL9 and CXCL10, which initiate the recruitment of protective natural killer (NK) cells in the infected trachea. In the absence of SIGN-R1, the recruitment and activation of NK cells is impaired, leading to uncontrolled viral proliferation. In sum, our results provide insight into the orchestration of the early cellular and molecular events involved in immune protection against influenza.

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Fig. 1: Influenza infection promotes early recruitment of IDCs to the trachea.
Fig. 2: Recruited IDCs are located in close proximity to the epithelial cell layer during influenza infection.
Fig. 3: Type I IFN is required for the production of CCL2, which recruits IDC precursors to the trachea.
Fig. 4: IDCs express the lectin receptor SIGN-R1, which recognizes influenza PR8 through binding to glycosylated viral proteins.
Fig. 5: SIGN-R1 is involved the production of inflammatory chemokines by IDCs and the recruitment of NK cells into the tracheal mucosa.
Fig. 6: SIGN-R1+ IDCs are required to control influenza infection in the trachea.

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Data availability

All data from this study are available from the corresponding author upon request.

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Acknowledgements

We thank D. Jarrossay for the provision of technical support and M. Uguccioni for critical discussion of the manuscript; J. Paulson (The Scripps Research Institute) for initially providing KO mice; D. Corti (Humabs) for providing the antibody FI6 and Core G of the Consortium for Functional Glycomics (S. Orr) for mouse phenotyping. This work was supported by the Swiss National Foundation grants, R’equipt (145038), Ambizione (148183) and grant 176124 to S.F.G., the European Commission Marie Curie Reintegration Grant (612742), and SystemsX.ch for a grant to D.U.P. (2013/124). This work was partly supported by Center for Research on Influenza Pathogenesis and National Institute of Allergy and Infectious Diseases-funded Center of Excellence on Influenza Research and Pathogenesis (contract number HHSN272201400008C).

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Authors and Affiliations

  1. Institute for Research in Biomedicine, Università della Svizzera italiana, Bellinzona, Switzerland

    Miguel Palomino-Segura, Laurent Perez, Yagmur Farsakoglu, Tommaso Virgilio, Irene Latino, Nikolaos Chatziandreou, Diego U. Pizzagalli, Federica Sallusto & Santiago F. Gonzalez

  2. Graduate School of Cellular and Molecular Sciences, Faculty of Medicine, University of Bern, Bern, Switzerland

    Miguel Palomino-Segura, Yagmur Farsakoglu & Tommaso Virgilio

  3. Light Microscopy STP, The Francis Crick Institute, London, UK

    Rocco D’Antuono

  4. Institute of Computational Science, Università della Svizzera italiana, Lugano, Switzerland

    Diego U. Pizzagalli

  5. Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Guojun Wang & Adolfo García-Sastre

  6. Global Health and Emerging Pathogen Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Guojun Wang & Adolfo García-Sastre

  7. Department of Medicine, Division of Infectious Diseases, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Adolfo García-Sastre

  8. Institute for Microbiology, ETH Zurich, Zurich, Switzerland

    Federica Sallusto

  9. Program in Cellular and Molecular Medicine, Boston Children’s Hospital and Harvard Medical School, Boston, MA, USA

    Michael C. Carroll

  10. Institut de Pharmacologie et de Biologie Structurale, Université de Toulouse CNRS, UPS, Toulouse, France

    Olivier Neyrolles

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Contributions

M.P.-S. and S.F.G. conceived the project, designed experiments and analysed and interpreted the results. M.P.-S. performed most of the experiments. L.P. designed, performed and analysed in vitro SIGN-R1–HA-interaction experiments with help from S.F.G. and M.P.-S. T.V. helped to perform confocal microscopy experiments. I.L. helped to study the in vitro chemokine production of IDCs. R.D. and D.U.P. analysed confocal microscopy data. G.W. and A.G.-S. generated the recombinant influenza virus. Y.F., N.C., F.S., M.C.C. and O.N. advised on the experiments, interpreted results, helped to develop protocols and contributed with reagents. S.F.G. and M.P.-S. wrote the manuscript with the help of N.C., L.P. and O.N. S.F.G. directed the study.

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Correspondence to Santiago F. Gonzalez.

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Palomino-Segura, M., Perez, L., Farsakoglu, Y. et al. Protection against influenza infection requires early recognition by inflammatory dendritic cells through C-type lectin receptor SIGN-R1. Nat Microbiol 4, 1930–1940 (2019). https://doi.org/10.1038/s41564-019-0506-6

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