SFTSV NSs protein is a novel tick antiviral RNAi response suppressor

Fares, M.; McFarlane, M.; Parry, R.; Arif, R.; Clarke, A. T.; Kamel, W.; Davies, K.; Bell-Sakyi, L.; Petit, M. J.; Schnettler, E.; Castello, A.; Kohl, A.; Brennan, B.

doi:10.1101/2025.08.14.670292

bioRxiv · 10.1101/2025.08.14.670292

SFTSV NSs protein is a novel tick antiviral RNAi response suppressor

Fares, M.·McFarlane, M.·Parry, R.·Arif, R.·Clarke, A. T.·Kamel, W.·Davies, K.·Bell-Sakyi, L.·Petit, M. J.·Schnettler, E.·Castello, A.·Kohl, A.·Brennan, B.

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Abstract

Severe fever with thrombocytopenia syndrome virus (SFTSV) is an emerging tick-borne phenuivirus causing high mortality in humans. While the non-structural protein NSs is dispensable for replication in interferon-deficient mammalian cells, we demonstrate for the first time that NSs is essential for viral replication in tick cells. SFTSV infection triggers canonical Dicer-2-mediated antiviral RNA interference (RNAi) in tick cells, producing virus-derived small interfering RNAs (siRNAs) that target viral transcripts for degradation. We show that NSs functions as a viral suppressor of RNAi by selectively engaging and depleting single-stranded RNAs derived from 22-nucleotide siRNAs, likely limiting their incorporation into RNA-induced silencing complexes (RISC). Complementation with a heterologous RNAi suppressor (p19 protein) partially rescues replication of NSs-deficient virus, validating the RNAi suppressive function of NSs. These findings reveal that successful tick-borne viral replication requires host-specific immune evasion strategies and establish NSs-mediated RNAi suppression as essential for SFTSV persistence in arthropod vectors. Significance StatementThis study reveals a critical requirement for SFTSV infection that differs between hosts. While the viral NSs protein is dispensable in interferon deficient mammalian cells, it is essential for replication in tick cells, the natural vectors of the virus. We show that NSs functions as a viral RNA silencing suppressor by associating with virus derived small RNAs and limiting their availability to the tick antiviral RNA interference machinery. This provides mechanistic insight into how tick-borne viruses evade arthropod immune defences through engagement of functional siRNAs rather than broad inhibition of RNA interference pathways. Together, these findings demonstrate that SFTSV employs distinct immune evasion strategies in different hosts and identify NSs as a key determinant of vector cell infection.

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Fares, M., McFarlane, M., Parry, R., Arif, R., Clarke, A. T., Kamel, W., Davies, K., Bell-Sakyi, L., Petit, M. J., Schnettler, E., Castello, A., Kohl, A., Brennan, B.. 2025-08-14. SFTSV NSs protein is a novel tick antiviral RNAi response suppressor. https://doi.org/10.1101/2025.08.14.670292

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