A natural variation in the RNA polymerase of severe fever with thrombocytopenia syndrome virus enhances viral replication and in vivo virulence

Abstract

Severe fever with thrombocytopenia syndrome (SFTS) is an emerging tick‐borne disease with high mortality in Eastern Asia. The disease is caused by the SFTS virus (SFTSV), also known as Dabie bandavirus, which has a segmented RNA genome consisting of L, M, and S segments. Previous studies have suggested differential viral virulence depending on the genotypes of SFTSV; however, the critical viral factor involved in the differential viral virulence is unknown. Here, we found a significant difference in viral replication in vitro and virulence in vivo between two Korean isolates belonging to the F and B genotypes, respectively. By generating viral reassortants using the two viral strains, we demonstrated that the L segment, which encodes viral RNA‐dependent RNA polymerase (RdRp), is responsible for the enhanced viral replication and virulence. Comparison of amino acid sequences and viral replication rates revealed a point variation, E251K, on the surface of RdRp to be the most significant determinant for the enhanced viral replication rate and in vivo virulence. The effect of the variation was further confirmed using recombinant SFTSV generated by reverse genetic engineering. Therefore, our results indicate that natural variations affecting the viral replicase activity could significantly contribute to the viral virulence of SFTSV.

Comparative analysis of the efficacy of vaccines using structural protein subunits of the severe fever with thrombocytopenia syndrome virus

“…Secondly, our study utilized structural antigens derived from SFTSV genotype D (KASJH strain), while the challenge virus, 2015-JJ01, belongs to genotype B. SFTSV, endemic in Eastern Asia, displays significant genotype heterogeneity, with at least 6 to 7 genotypes identified ( Zu et al, 2022 ). Considering this diversity, the severity of disease and the efficacy of protection could vary based on the vaccine antigens and the challenge virus derived from different strains ( Yu et al, 2019 ; Yun et al, 2020 ; Dai et al, 2022 ; Jeon et al, 2023 ). Therefore, evaluating the potential cross-reactivity and heterologous protection against diverse genotypes will be crucial in future studies.…”

“…SFTS symptoms include high fever, thrombocytopenia, leukocytopenia, and in severe cases, multiorgan dysfunction. Reported case fatality rates in China, Japan, and South Korea are ranging from 10 to 30%, depending on patients’ age, sex, and endemic regions ( He et al, 2020 ; Miao et al, 2021 ; Jeon et al, 2023 ), with the virus’s presence and its antibodies also noted in various Southeast Asian countries, raising concerns about its spread ( Tran et al, 2019 ; Peng et al, 2020 ; Win et al, 2020 ; Rattanakomol et al, 2022 ).…”