Severe fever with thrombocytopenia syndrome virus NSs: a multifaceted viral protein in host-virus interactions.

Severe fever with thrombocytopenia syndrome virus (SFTSV) is a highly lethal tick-borne bunyavirus, and its nonstructural protein NSs is the engine driving viral pathogenesis. Far beyond a simple accessory protein, NSs acts as a master manipulator of the host: it shuts down interferon defenses, rewires inflammatory signaling, and creates an immunosuppressive environment that favors viral survival. At the same time, NSs reshapes cellular physiology by halting the cell cycle, reprogramming stress and antioxidant pathways, dismantling antiviral granules, and hijacking metabolic organelles such as lipid droplets and autophagosomes to build replication-permissive niches. Remarkably, NSs also functions as a cross-kingdom suppressor of RNA interference, disarming antiviral defenses in both mammalian hosts and tick vectors to ensure efficient replication and transmission. This convergence of immune evasion, cellular reprogramming, and vector adaptation underscores NSs as the central determinant of SFTSV virulence and a striking example of how a single viral protein can orchestrate complex host-pathogen interactions.