Abstract

Severe fever with thrombocytopenia syndrome phlebovirus (SFTSV), listed in the World Health Organization Prioritized Pathogens, is an emerging phlebovirus with a high fatality1,2,3,4. Owing to the lack of therapies and vaccines5,6, there is a pressing need to understand SFTSV pathogenesis. SFSTV non-structural protein (NSs) has been shown to block type I interferon induction7,8,9,10,11 and facilitate disease progression12,13. Here, we report that SFTSV-NSs targets the tumour progression locus 2 (TPL2)–A20-binding inhibitor of NF-κB activation 2 (ABIN2)–p105 complex to induce the expression of interleukin-10 (IL-10) for viral pathogenesis. Using a combination of reverse genetics, a TPL2 kinase inhibitor and Tpl2−/− mice showed that NSs interacted with ABIN2 and promoted TPL2 complex formation and signalling activity, resulting in the marked upregulation of Il10 expression. Whereas SFTSV infection of wild-type mice led to rapid weight loss and death, Tpl2−/− mice or Il10−/− mice survived an infection. Furthermore, SFTSV-NSs P102A and SFTSV-NSs K211R that lost the ability to induce TPL2 signalling and IL-10 production showed drastically reduced pathogenesis. Remarkably, the exogenous administration of recombinant IL-10 effectively rescued the attenuated pathogenic activity of SFTSV-NSs P102A, resulting in a lethal infection. Our study demonstrates that SFTSV-NSs targets the TPL2 signalling pathway to induce immune-suppressive IL-10 cytokine production as a means to dampen the host defence and promote viral pathogenesis.

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The data that support the findings of this study are available from the corresponding author upon request.

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References

  1. 1.

    Gai, Z. T. et al. Clinical progress and risk factors for death in severe fever with thrombocytopenia syndrome patients. J. Infect. Dis. 206, 1095–1102 (2012).

  2. 2.

    Liu, S. et al. Systematic review of severe fever with thrombocytopenia syndrome: virology, epidemiology, and clinical characteristics. Rev. Med. Virol. 24, 90–102 (2014).

  3. 3.

    Guardado-Calvo, P. & Rey, F. A. The envelope proteins of the Bunyavirales. Adv. Virus Res. 98, 83–118 (2017).

  4. 4.

    Yu, X. J. et al. Fever with thrombocytopenia associated with a novel bunyavirus in China. N. Engl. J. Med. 364, 1523–1532 (2011).

  5. 5.

    Oh, W. S. et al. Plasma exchange and ribavirin for rapidly progressive severe fever with thrombocytopenia syndrome. Int. J. Infect. Dis. 18, 84–86 (2014).

  6. 6.

    Xie, Q. X., Li, X., Cheng, J. & Shao, Y. Multiple organ damage caused by a novel tick-borne bunyavirus: a case report. J. Vector Borne Dis. 50, 314–317 (2013).

  7. 7.

    Chaudhary, V. et al. Suppression of type I and type III IFN signalling by NSs protein of severe fever with thrombocytopenia syndrome virus through inhibition of STAT1 phosphorylation and activation. J. Gen. Virol. 96, 3204–3211 (2015).

  8. 8.

    Ning, Y. J. et al. Disruption of type I interferon signaling by the nonstructural protein of severe fever with thrombocytopenia syndrome virus via the hijacking of STAT2 and STAT1 into inclusion bodies. J. Virol. 89, 4227–4236 (2015).

  9. 9.

    Qu, B. et al. Suppression of the interferon and NF-κB responses by severe fever with thrombocytopenia syndrome virus. J. Virol. 86, 8388–8401 (2012).

  10. 10.

    Santiago, F. W. et al. Hijacking of RIG-I signaling proteins into virus-induced cytoplasmic structures correlates with the inhibition of type I interferon responses. J. Virol. 88, 4572–4585 (2014).

  11. 11.

    Moriyama, M. et al. Two conserved amino acids within the NSs of severe fever with thrombocytopenia syndrome phlebovirus are essential for anti-interferon activity. J. Virol. 92, e00706-18 (2018).

  12. 12.

    Liu, M. M., Lei, X. Y., Yu, H., Zhang, J. Z. & Yu, X. J. Correlation of cytokine level with the severity of severe fever with thrombocytopenia syndrome. Virol. J. 14, 6 (2017).

  13. 13.

    Deng, B. et al. Cytokine and chemokine levels in patients with severe fever with thrombocytopenia syndrome virus. PLoS ONE 7, e41365 (2012).

  14. 14.

    Brennan, B. et al. Reverse genetics system for severe fever with thrombocytopenia syndrome virus. J. Virol. 89, 3026–3037 (2015).

  15. 15.

    Matsuno, K. et al. Animal models of emerging tick-borne phleboviruses: determining target cells in a lethal model of SFTSV infection. Front. Microbiol. 8, 104 (2017).

  16. 16.

    Song, P. et al. Deficient humoral responses and disrupted B-cell immunity are associated with fatal SFTSV infection. Nat. Commun. 9, 3328 (2018).

  17. 17.

    Iyer, S. S. & Cheng, G. Role of interleukin 10 transcriptional regulation in inflammation and autoimmune disease. Crit. Rev. Immunol. 32, 23–63 (2012).

  18. 18.

    Brooks, D. G., Lee, A. M., Elsaesser, H., McGavern, D. B. & Oldstone, M. B. IL-10 blockade facilitates DNA vaccine-induced T cell responses and enhances clearance of persistent virus infection. J. Exp. Med. 205, 533–541 (2008).

  19. 19.

    Brooks, D. G. et al. Interleukin-10 determines viral clearance or persistence in vivo. Nat. Med. 12, 1301–1309 (2006).

  20. 20.

    Redpath, S., Ghazal, P. & Gascoigne, N. R. Hijacking and exploitation of IL-10 by intracellular pathogens. Trends Microbiol. 9, 86–92 (2001).

  21. 21.

    Wagner, S. et al. Ubiquitin binding mediates the NF-κB inhibitory potential of ABIN proteins. Oncogene 27, 3739–3745 (2008).

  22. 22.

    Jain, A. et al. Probing cellular protein complexes using single-molecule pull-down. Nature 473, 484–488 (2011).

  23. 23.

    Lang, V. et al. ABIN-2 forms a ternary complex with TPL-2 and NF-κB1 p105 and is essential for TPL-2 protein stability. Mol. Cell. Biol. 24, 5235–5248 (2004).

  24. 24.

    Aoki, M. et al. The human cot proto-oncogene encodes two protein serine/threonine kinases with different transforming activities by alternative initiation of translation. J. Biol. Chem. 268, 22723–22732 (1993).

  25. 25.

    Saraiva, M. & O’Garra, A. The regulation of IL-10 production by immune cells. Nat. Rev. Immunol. 10, 170–181 (2010).

  26. 26.

    Peng, C. et al. Decreased monocyte subsets and TLR4-mediated functions in patients with acute severe fever with thrombocytopenia syndrome (SFTS). Int. J. Infect. Dis. 43, 37–42 (2016).

  27. 27.

    Brennan, B., Rezelj, V. V. & Elliott, R. M. Mapping of transcription termination within the S segment of SFTS phlebovirus facilitated generation of NSs deletant viruses. J. Virol. 91, e00743-17 (2017).

  28. 28.

    Sun, Y. Y. et al. Nonmuscle myosin heavy chain IIA is a critical factor contributing to the efficiency of early infection of severe fever with thrombocytopenia syndrome virus. J. Virol. 88, 237–248 (2014).

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Acknowledgements

This work was partly supported by CA200422, CA180779, DE023926, DE027888, AI073099, AI116585, AI129496, AI140718, AI140705, the Hastings Foundation and the Fletcher Jones Foundation (J.U.J.), the Wellcome Trust Senior Investigator Award 099220/Z/12/Z and the Wellcome Trust/Royal Society Henry Dale Fellow (B.B.), the Korean National Research Foundation MEST 2015020957 (J.-S.L.), the National Science and Technology Major Project China 2013ZX09509102 (W.L.) and the Korea Health Industry Development Institute HI15C2817 (Y.-K.C.).

Author information

Affiliations

  1. Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Zilkha Neurogenetic Institute, Los Angeles, CA, USA

    • Younho Choi
    • , Ji-Seung Yoo
    • , Raghavendra Sumanth Pudupakam
    • , Suan-Sin Foo
    • , Woo-Jin Shin
    • , Sally B. Chen
    •  & Jae U. Jung
  2. Department of Microbiology and Zoonotic Infectious Diseases Research Center, College of Medicine and Medical Research Institute, Chungbuk National University, Cheongju, South Korea

    • Su-Jin Park
    •  & Young-Ki Choi
  3. National Institute of Biological Sciences, Beijing, ZGC Life Science Park, Changping, Beijing, China

    • Yinyan Sun
    •  & Wenhui Li
  4. Molecular Oncology Research Institute, Tuft Medical School, Boston, MA, USA

    • Philip N. Tsichlis
  5. Division of Arboviruses, National Research Institute of Health, Korea Centers for Disease Control and Prevention, Cheongju, South Korea

    • Won-Ja Lee
  6. College of Veterinary Medicine, Chungnam National University, Daejeon, South Korea

    • Jong-Soo Lee
  7. MRC–University of Glasgow Centre for Virus Research, Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK

    • Benjamin Brennan

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Contributions

Y.C. performed and analysed all of the experiments, prepared the figures and wrote the first draft of the manuscript. S.-J.P., Y.S., J.-S.Y., R.S.P., S.-S.F., W.-J.S., S.B.C., P.N.T., W.J.L., J.-S.L., W.L., B.B. and Y.-K.C. collaborated in the experimental design and interpretation. S.-J.P. tested the human patient samples. Y.S. and W.L. provided the SFTSV-Gn antibody. J.-S.Y., R.S.P. and W.-J.S. worked in BSL3 for the viral infection studies. S.B.C. performed the SiMPull assay. S.-S.F. designed the whole-blood infection study. P.N.T. provided the mouse strain. W.J.L. provide the human patient samples. B.B. provided materials for reverse genetics and the viral strains. Y.C. and J.U.J. jointly conceived the experimental design, interpreted the results and wrote subsequent drafts of the manuscript.

Competing interests

The authors declare no competing interests.

Corresponding author

Correspondence to Jae U. Jung.

Supplementary information

  1. Supplementary Information

    Supplementary Figures 1–9, Supplementary Tables 1–4 and Uncropped Blots.

  2. Reporting Summary

  3. Supplementary Data

    Supplementary Data 1: NanoString data from macrophage cell lines with LPS treatment; Supplementary Data 2: NanoString data from spleen of SFTSV infected Ifnar−/− mice.

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DOI

https://doi.org/10.1038/s41564-018-0329-x