Reader TTS

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.

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

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).

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

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

Miguel Palomino-Segura, Yagmur Farsakoglu & Tommaso Virgilio

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

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

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

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

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

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

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

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.

Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Anyone you share the following link with will be able to read this content: