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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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


  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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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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