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A Single Residue in the Gc Protein Dictates Neutralization Sensitivity and Virulence in SFTSV

ABSTRACT: Severe fever with thrombocytopenia syndrome virus (SFTSV), a WHO priority pathogen, causes hemorrhagic fever with up to 30% case fatality and lacks approved vaccines or therapeutics. Here, we isolated Gc-specific monoclonal antibodies H2, H4, and H12. H2 potently neutralized endemic Chinese SFTSV strains but failed against the heterologous NB24 strain. Fine epitope mapping identified Arg577 within Gc domain I as the core of H2's conformational epitope. Reverse genetics demonstrated that Arg577 is both necessary for H2 binding and sufficient to confer neutralization susceptibility. Beyond immune recognition, residue 577 critically governed viral replication fitness and pathogenesis. In virulent HBMC, Arg577 was essential for efficient replication, assembly and overall viral fitness; in attenuated NB24 (native lysine), introducing Arg577 enhanced progeny production and virulence. Combining H2 with H12 overcame H2's narrow neutralization, achieving broad protection. Our study establishes Arg577 as a central regulator of SFTSV pathogenicity and informs dual-antibody therapy development.

ORGANISM(S): Chlorocebus sabaeus

PROVIDER: GSE346288 | GEO | 2026/09/07

REPOSITORIES: GEO

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Project description:RNA modification plays a crucial role in the regulation of various diseases and viral infections. ADAR1 (adenosine deaminase 1) is a key RNA editing enzyme that can convert adenosine (A) into the modified base inosine (I). This RNA modification has been confirmed to regulate the biological processes of various diseases and viruses. In our previous study on patients with thrombocytopenia syndrome, we conducted a longitudinal sampling study of transcriptomics and epigenetics (Nat. Commun., 2021, 12:5629). In this study, through the analysis of patient RNA-seq, we found that in patients infected with SFTSV, the expression of ADAR1 increased, and it gradually decreased with the recovery of the patients. By constructing cell models and conducting RNA sequencing analysis, we also obtained results similar to those from clinical samples. We found that ADAR1 knockdown promoted the replication of Bunyavirus (SFTSV), while overexpression inhibited virus replication. Further miRNA sequencing analysis revealed that after ADAR1 knockdown, some miRNAs with differential expression were produced, and the target genes of these differentially expressed miRNAs were closely related to neutrophil-mediated immune signaling pathways. These differentially expressed miRNAs may be due to ADAR1 editing the adenosine (A) in the double-stranded region of miRNA precursors to inosine (I), thereby changing the structure of dsRNA and making it difficult for Drosha or Dicer to obtain, thereby reducing the production of miRNAs. Considering these phenomena, we speculate that in the ADAR1 knockdown state, the changes in miRNA expression levels lead to the downregulation of genes involved in neutrophil-mediated immune signaling pathways, potentially causing neutrophil-mediated immune function impairment, thereby enhancing SFTSV replication. These findings provide new insights into the role of ADAR1 in SFTSV replication and immune signaling pathways, and provide a theoretical basis for the development of treatment strategies targeting ADAR1.

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A Single Residue in the Gc Protein Dictates Neutralization Sensitivity and Virulence in SFTSV

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