Comparison of the pathogenicity in type I interferon receptor deficient A129 mice and characterization of amino acid substitutions among severe fever with thrombocytopenia syndrome virus strains.

Severe fever with thrombocytopenia syndrome virus (SFTSV) is an emerging tick-borne zoonotic pathogen endemic to Asian countries, including Japan. We previously demonstrated that a pair of amino acid residues, Gly581 and Ser934 in the Gc of SFTSV, are key determinants of virulence in type I interferon receptor-deficient A129 mice. However, whether additional viral factors contribute to strain-dependent differences in pathogenicity remains unclear. In this study, we further observed the pathogenicity of fourteen SFTSV strains, including newly isolated strains from SFTS cat cases, in A129 mice. Fatality rates ranged from 20% to 100%. Notably, all strains, including those with low fatality, possessed the virulent Gly581 and Ser934, suggesting that other substitutions influence to the pathogenicity. Focusing on Sh-F149 and Yg-F197 with reduced virulence (40% fatality), we found unique amino acid substitutions. Sh-F149 possessed Ile745 in the Gc, and Yg-F197 exhibited Thr172 in the non-structural proteins, Gly20 and Arg113 in the Gn, and Arg307, Val371, Pro374, and Asn1610 in the RNA-dependent RNA polymerase. No significant differences in viral growth kinetics were observed among strains in Vero E6 and TLT cells, and phylogenetic analysis showed that all strains belonged predominantly to genotype J1. These findings indicate that neither in vitro replication efficiency nor genotype alone accounts for virulence differences in A129 mice. Taken together, our results suggest that strain-specific amino acid substitutions contribute to SFTSV pathogenicity and provide a basis for future mechanistic studies.