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.
Subscribe to Journal
Get full journal access for 1 year
only $5.17 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
The data that support the findings of this study are available from the corresponding author upon request.
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).
Liu, S. et al. Systematic review of severe fever with thrombocytopenia syndrome: virology, epidemiology, and clinical characteristics. Rev. Med. Virol. 24, 90–102 (2014).
Guardado-Calvo, P. & Rey, F. A. The envelope proteins of the Bunyavirales. Adv. Virus Res. 98, 83–118 (2017).
Yu, X. J. et al. Fever with thrombocytopenia associated with a novel bunyavirus in China. N. Engl. J. Med. 364, 1523–1532 (2011).
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).
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).
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).
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).
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).
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).
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).
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).
Deng, B. et al. Cytokine and chemokine levels in patients with severe fever with thrombocytopenia syndrome virus. PLoS ONE 7, e41365 (2012).
Brennan, B. et al. Reverse genetics system for severe fever with thrombocytopenia syndrome virus. J. Virol. 89, 3026–3037 (2015).
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).
Song, P. et al. Deficient humoral responses and disrupted B-cell immunity are associated with fatal SFTSV infection. Nat. Commun. 9, 3328 (2018).
Iyer, S. S. & Cheng, G. Role of interleukin 10 transcriptional regulation in inflammation and autoimmune disease. Crit. Rev. Immunol. 32, 23–63 (2012).
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).
Brooks, D. G. et al. Interleukin-10 determines viral clearance or persistence in vivo. Nat. Med. 12, 1301–1309 (2006).
Redpath, S., Ghazal, P. & Gascoigne, N. R. Hijacking and exploitation of IL-10 by intracellular pathogens. Trends Microbiol. 9, 86–92 (2001).
Wagner, S. et al. Ubiquitin binding mediates the NF-κB inhibitory potential of ABIN proteins. Oncogene 27, 3739–3745 (2008).
Jain, A. et al. Probing cellular protein complexes using single-molecule pull-down. Nature 473, 484–488 (2011).
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).
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).
Saraiva, M. & O’Garra, A. The regulation of IL-10 production by immune cells. Nat. Rev. Immunol. 10, 170–181 (2010).
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).
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).
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).
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.).
The authors declare no competing interests.
Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Cite this article
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
Entomological Research (2020)
Current Opinion in Virology (2020)
Journal of Clinical Investigation (2020)
Severe Fever with Thrombocytopenia Syndrome Virus NSs Interacts with TRIM21 To Activate the p62-Keap1-Nrf2 Pathway
Journal of Virology (2019)