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Structural basis for human respiratory syncytial virus NS1-mediated modulation of host responses

Nature Microbiology volume 2, Article number: 17101 (2017) Cite this article

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Abstract

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 antagonists3–6; 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.

Human respiratory syncytial virus (hRSV) is a major cause of severe respiratory infections in children and a significant contributor to morbidity and mortality for the elderly and immune-compromised individuals. The virus causes 130,000 cases of clinical infection in children under five years of age in the USA alone1,2. Currently, we lack sufficient knowledge and understanding of several outcomes that are observed during hRSV infections, including complications arising from partial immunity to hRSV infections, reduced immune responses in infants with maternal antibodies, and vaccine enhancement of disease7. We also lack a complete view of the host–viral interactions that occur in response to hRSV infection8. As a consequence, only limited effective prophylactic or therapeutic approaches are currently available to attenuate hRSV infections9.

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Figure 1: Sequence alignment of NS1 proteins from the genus Orthopneumovirus.
Figure 2: hRSV NS1 is a structural paralogue of hRSV matrix (M) protein.
Figure 3: hRSV NS1 mutations impact NS1 function.
Figure 4: NS1 unique regions are important for modulating host responses.

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Acknowledgements

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

  1. Srirupa Chatterjee, Gaya K. Amarasinghe and Daisy W. Leung: These authors contributed equally to this work as first authors

  2. Priya Luthra, Ekaterina Esaulova and Eugene Agapov: These authors contributed equally to this work as second authors.

Authors and Affiliations

  1. Department of Pathology and Immunology, Washington University School of Medicine, St Louis, 63110, Missouri, 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, 30303, Georgia, USA

    Priya Luthra & Christopher F. Basler

  3. Computer Technologies Department, ITMO University, 197101, Saint Petersburg, Russia

    Ekaterina Esaulova

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

    Eugene Agapov & Michael J. Holtzman

  5. Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, 10029, New York, USA

    Benjamin C. Yen

  6. Departments of Biophysics and Biochemistry, University of Texas Southwestern Medical Center, 75390, Texas, USA

    Dominika M. Borek

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

    Anuradha Mittal & Rohit V. Pappu

  8. Division of Infectious Diseases, Emory University School of Medicine, Atlanta, 30322, Georgia, USA

    Martin L. Moore

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Contributions

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.

Corresponding authors

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

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Chatterjee, S., Luthra, P., Esaulova, E. et al. Structural basis for human respiratory syncytial virus NS1-mediated modulation of host responses. Nat Microbiol 2, 17101 (2017). https://doi.org/10.1038/nmicrobiol.2017.101

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