Human respiratory syncytial virus (hRSV) is a major cause of morbidity and mortality in the paediatric, elderly and immune-compromised populations1,2. A gap in our understanding of hRSV disease pathology is the interplay between virally encoded immune antagonists and host components that limit hRSV replication. hRSV encodes for non-structural (NS) proteins that are important immune antagonists3,​4,​5,​6; however, the role of these proteins in viral pathogenesis is incompletely understood. Here, we report the crystal structure of hRSV NS1 protein, which suggests that NS1 is a structural paralogue of hRSV matrix (M) protein. Comparative analysis of the shared structural fold with M revealed regions unique to NS1. Studies on NS1 wild type or mutant alone or in recombinant RSVs demonstrate that structural regions unique to NS1 contribute to modulation of host responses, including inhibition of type I interferon responses, suppression of dendritic cell maturation and promotion of inflammatory responses. Transcriptional profiles of A549 cells infected with recombinant RSVs show significant differences in multiple host pathways, suggesting that NS1 may have a greater role in regulating host responses than previously appreciated. These results provide a framework to target NS1 for therapeutic development to limit hRSV-associated morbidity and mortality.

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The authors thank H. Virgin, M. Diamond, T. Ellenberger and J. Payton, M. Dinauer and E.E.L. Amarasinghe for discussions and J. Huh for technical support. Work in our laboratories is supported, in part, by NIH grants (R01AI107056 (to D.W.L.), R01AI123926 (to G.K.A.), R01AI114654 (to C.F.B.), U191099565 (G.K.A. is the PI of the subaward from a U19 grant for which Ting is the PI), U19AI109945 (to C.F.B.), U19AI109664 (to C.F.B.), U19AI070489 (to M.J.H.), R01AI111605 (to M.J.H.), R01 AI130591 (to M.J.H.), R01AI087798 (to M.L.M.), U19AI095227 (to M.L.M.) and T32-CA09547-37 (D.S.J. is the recipient of a training award from a T32 grant for which Allen is the PI)), the Department of Defense, Defense Threat Reduction Agency grants HDTRA1-16-0033 (to C.F.B.) and HDTRA1-16-0033 (to C.F.B.), the National Science Foundation MCB-1121867 (to R.V.P.) and the Children's Discovery Institute PD-II-2013-272 (to G.K.A.). S.C. is funded in part by an American Heart Association Postdoctoral Fellowship (15POST25140009). We thank members in the Amarasinghe, Leung, Basler, Artyomov and Holtzman laboratories and S. Ginell, N. Duke, R. Alkire, K. Lazarski, M. Ficner-Radford, Y. Kim and A. Joachimiak at Argonne National Laboratory SBC Sector 19. Use of Argonne National Laboratory Structural Biology Center beam lines at the Advanced Photon Source is supported by the US Department of Energy under contract DE-AC02-06CH11357. The content of the information does not necessarily reflect the position or the policy of the federal government and no official endorsement should be inferred.

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Author notes

    • Srirupa Chatterjee
    • , Gaya K. Amarasinghe
    •  & Daisy W. Leung

    These authors contributed equally to this work as first authors

    • Priya Luthra
    • , Ekaterina Esaulova
    •  & Eugene Agapov

    These authors contributed equally to this work as second authors.


  1. Department of Pathology and Immunology, Washington University School of Medicine, St Louis, Missouri 63110, USA

    • Srirupa Chatterjee
    • , Ekaterina Esaulova
    • , Megan R. Edwards
    • , David S. Jordan
    • , Parameshwar Ramanan
    • , Maxim N. Artyomov
    • , Gaya K. Amarasinghe
    •  & Daisy W. Leung
  2. Center for Microbial Pathogenesis, Institute for Biomedical Sciences, Georgia State University, Atlanta, Georgia 30303, USA

    • Priya Luthra
    •  & Christopher F. Basler
  3. Computer Technologies Department, ITMO University, Saint Petersburg 197101, Russia

    • Ekaterina Esaulova
  4. Department of Medicine, Washington University School of Medicine, St Louis, Missouri 63110, USA

    • Eugene Agapov
    •  & Michael J. Holtzman
  5. Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA

    • Benjamin C. Yen
  6. Departments of Biophysics and Biochemistry, University of Texas Southwestern Medical Center, Texas 75390, USA

    • Dominika M. Borek
  7. Department of Biomedical Engineering, Center for Biological Systems Engineering, Washington University in St. Louis, St. Louis, Missouri 63130, USA

    • Anuradha Mittal
    •  & Rohit V. Pappu
  8. Division of Infectious Diseases, Emory University School of Medicine, Atlanta, Georgia 30322, USA

    • Martin L. Moore


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G.K.A. and D.W.L. conceived and designed the overall study, with input from the co-authors. S.C., P.L., E.E., E.A., B.C.Y., D.M.B., M.R.E., A.M., P.R., D.S.J., G.K.A. and D.W.L. performed research. M.L.M. provided the wild-type virus. All co-authors analysed the results. R.V.P., M.J.H., M.L.M., M.A., C.F.B., G.K.A. and D.W.L. designed and coordinated studies within each group. C.F.B., G.K.A. and D.W.L. wrote the manuscript with input from all co-authors. All authors analysed the results, and read and approved the manuscript for submission.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Gaya K. Amarasinghe or Daisy W. Leung.

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