Severe fever with thrombocytopenia syndrome phlebovirus non-structural protein activates TPL2 signalling pathway for viral immunopathogenesis
Nature microbiology, 2019•nature.com
Severe fever with thrombocytopenia syndrome phlebovirus (SFTSV), listed in the World
Health Organization Prioritized Pathogens, is an emerging phlebovirus with a high fatality,,–.
Owing to the lack of therapies and vaccines,, there is a pressing need to understand SFTSV
pathogenesis. SFSTV non-structural protein (NSs) has been shown to block type I interferon
induction,,,–and facilitate disease progression,. Here, we report that SFTSV-NSs targets the
tumour progression locus 2 (TPL2)–A20-binding inhibitor of NF-κB activation 2 (ABIN2) …
Health Organization Prioritized Pathogens, is an emerging phlebovirus with a high fatality,,–.
Owing to the lack of therapies and vaccines,, there is a pressing need to understand SFTSV
pathogenesis. SFSTV non-structural protein (NSs) has been shown to block type I interferon
induction,,,–and facilitate disease progression,. Here, we report that SFTSV-NSs targets the
tumour progression locus 2 (TPL2)–A20-binding inhibitor of NF-κB activation 2 (ABIN2) …
Abstract
Severe fever with thrombocytopenia syndrome phlebovirus (SFTSV), listed in the World Health Organization Prioritized Pathogens, is an emerging phlebovirus with a high fatality, , –. Owing to the lack of therapies and vaccines,, there is a pressing need to understand SFTSV pathogenesis. SFSTV non-structural protein (NSs) has been shown to block type I interferon induction, , , – and facilitate disease progression,. 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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