Severe fever with thrombocytopenia syndrome phlebovirus non-structural protein activates TPL2 signalling pathway for viral immunopathogenesis

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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Fig. 1: SFTSV-NSs-mediated alteration of host gene expression.
Fig. 2: NSs activates TPL2 ternary complex formation through interaction with ABIN2.
Fig. 3: SFTSV-NSs induces IL-10 expression by activating the TPL2 signalling pathway.
Fig. 4: NSs-mediated activation of the TPL2 signalling pathway is required for SFTSV-induced lethal phenotype.

Data availability

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

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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.).

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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.

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Correspondence to Jae U. Jung.

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Supplementary Information

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

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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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Choi, Y., Park, S., Sun, Y. et al. Severe fever with thrombocytopenia syndrome phlebovirus non-structural protein activates TPL2 signalling pathway for viral immunopathogenesis. Nat Microbiol 4, 429–437 (2019). https://doi.org/10.1038/s41564-018-0329-x

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